Processes for the preparation of derivatives of 4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuro-[3a, 3, 2-ef][2]benzazepine

ABSTRACT

The invention relates to processes for the preparation of 4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine, or derivatives thereof. Furthermore, the invention also relates to the compounds formed during the preparation of 4a, 5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine.

This is a divisional of co-pending application Ser. No. 09/296,609,filed on Apr. 23, 1999, which is a divisional of co-pending applicationSer. No. 08/839,350, filed on Apr. 18, 1997, now U. S. Pat. No.6,043,359, which is a continuation-in-part of patent application Ser.No. 08/487,102, filed on Jun. 7,1995, now abandoned.

The invention relates to processes for the preparation of derivatives of4a, 5,9,10,11,12-hexahydro-6H-benzofuro [3a,3,2-ef] [2]benzazepine, ofthe general formula (I)

or of salts thereof, wherein R₂, R₄, X₁, X₂, Y₁ and Y₂ are eitheridentical or different and are hydrogen, fluorine, chlorine, bromine,iodine, a hydroxyl or alkoxy group, a lower, optionally branched alkylgroup which is optionally substituted by, for example, at least onehalogen, a lower, optionally branched alkenyl, group, a lower,optionally branched alkynyl group, an optionally substituted aryl,aralkyl or aryloxyalkyl group, the alkyl chain of which is optionallybranched and the aromatic nucleus of which is optionally substituted,formyl or unbranched or branched alkylcarbonyl, arylcarbonyl,arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl,aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl whichare unsubstituted or substituted by one or more halogens, or Y₁ and Y₂together are =0 and wherein A is a benzene nucleus which is optionallymono- or polysubstituted by at least one lower, optionally branchedalkyl group, at least one lower, optionally branched alkene group, atleast one lower, optionally branched alkyne group, at least one lower,optionally branched alkoxy group, by fluorine, chlorine, bromine oriodine or by several identical or different halogens, at least one alkylgroup substituted by one halogen or by several identical or differenthalogens, such as chloromethyl and trifluoromethyl, at least oneoptionally substituted aralkyl group and/or at least one hydroxyl group,primary, secondary or tertiary amino group, nitro group, nitrile group,alkylamino group, arylamino group, aldehyde group, carboxylic acid groupor all derivatives of the carboxylic acid group, such as eaters, asidesand halides.

The invention furthermore relates to processes for the preparation ofderivatives of 4a,3,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine, of the general formula (II)

wherein R₂, R₄, X₁, X₂, Y₁, and Y₂ and A have the meanings given abovefor formula (I), Z⁻ is an organic anion of a pharmaceutically usefulacid, such as tartrate, lactate, citrate, acetate or maleate, or aninorganic anion, such as fluoride, chloride, bromide, iodide, sulfate,phosphate or chlorate, R₅ is hydrogen, formyl, unbranched or branchedalkyl, alkenyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl oraralkylcarbonyl which are unsubstituted or substituted by at least onehalogen, or branched or branched alkyloxycarbonyl aryloxycarbonyl,aralkyloxycarbonyl, alkylsulfonyl, arylsulfonyl or aralkylsulfonyl whichare unsubstituted or substituted by one or more halogens.

Preferred meanings of the substituents R₁-R₆, X_(1,2) Y_(1,2) are R₁,R₂, R₃, R₆: hydrogen, unbranched or branched alkyl, alkenyl, aryl,aralkyl, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl which areunsubstituted or substituted by one or more halogens, or any combinationof these radicals, X₁, X₂: H, F, Cl, Br, I⁻, t-butyl and anycombination, Y₁, Y₂: H, O-R₆, and Y₁ and Y₂=0, R₄, R₅: the preferredmeanings mentioned for R₁, R₂, R₃, R₆ and unbranched or branchedalkyloxycarbonyl, aryloxycarbonyl aralkyloxycarbonyl, alkylsulfonyl,arylsulfonyl or aralkylsulfonyl which are unsubstituted or substitutedby one or more halogens.

Galanthamine is an alkaloid of high pharmacological activity whichoccurs chiefly in plants of the Amaryllidaceae type. Its action as aselective acetylcholinesterase inhibitor and its associated use forAlzheimer's diseases are to be emphasized in particular. Galanthaminehas been isolated to date from the caucasian snowdrop Galanthus woronoyiin amounts of a few kg annually at a cost of more than US$ 30,000/kg.Galanthamine syntheses have been known in principle since the end of thenineteen-sixties, but long, uneconomical reaction paths with pooroverall yields have been used.

The synthesis of some compounds of the general formulae (I) and (II)given above is known per se and described in the literature. ThusN-(3-hydroxy-4-methoxyphenyl)-N-methyl -4-hydroxy -phenylethylamine hasbeen subjected to oxidative cyclization with the aid of variousoxidizing agents to give narwedine derivatives (narwedine is theprecursor to galanthamine, but already has the ring structurecharacteristic of galanthamine) [Lit. 1-2], the yields as a rule beingless than 1% of theory. Although the structure could thus bedemonstrated galanthamine could not be prepared in kg amounts ofpharmaceutical interest.

Optimized processes (above all Kametani, Lit. 3-7,22) describe thiscyclization an N-methyl-benzamide and phenylacetamide derivatives inyields of up to 40%, but the poor overall yields render industrialutilization impossible. The literature furthermore reports thecyclization of N,N-disubstituted phenylethylamine derivatives (Lit. 8)and electrochemical (Lit. 9-12), microbiological, enzymatic (Lit. 8) andbiomimetic methods (Lit. 14-15). Lit. 23 describes the preparation ofnarwedine from isovanillin in an overall yield of 44%, but the use ofequimolar amounts of palladium and also thallium trifluoroacetate renderthis synthesis uneconomical. (+/−) Narwedine obtained by this route(Lit. 23) is enriched in the desired (−) narwedine in Lit. 24 andconverted into galanthamine with L-Selektride in a good yield.

Lit. 8 proposes a synthesis in which the oxidative cyclization isdescribed with a yield of 21%, but separation of the enantiomers isabsent. The reduction of bromonarwedine with LiAlH₄ in THF to form a53:31 diastereomer mixture of (+/−) galanthamine and (+/−)epigalanthamine is also known.

The invention is based an the object of developing a synthesis processwith which larger amounts of the title substances can be prepared in areproducible manner and in improved yields both of the individual stepsand of the overall yield.

This object is achieved according to the invention by the processesaccording to claim 1 and 2, the sub-claims relating to preferred andadvantageous variants and embodiments of the invention. In particular,the following measures of the invention have proved to be advantageous:

Replacement of halogenated solvents, for example chloroform, by toluene.Halogenated solvents are nowadays scarcely still employed as industrialsolvents because of their toxicity, the difficulties of their disposaland their ecological unacceptability. Toluene, in contrast, does nothave these disadvantages.

Working up by extraction requires organic solvents. With the invention,the working up operations of most stages can be optimized such that thereaction product can usually be obtained in crystalline form from thesolution. Chromatographic purification stages or extractions can thusmostly be avoided.

Furthermore, the yields can be reproduced within a very narrow range inthe invention by improving the parameters and the purity of the mainproducts and the content of by-products can be defined according tothese reactions. Improved and reproducible yields of the individualstages and of, the overall yield are possible with the process of theinvention. The invention provides, inter alia, a process in whichbromoformylnarwedine is reduced with reducing agents. L-Selektride canbe used as the reducing agent, the reduction leadingdiastereoselectively to N-demethylbromogalanthamine in a high yield (forexample 85%), which can be converted into (±) galanthamine byN-methylation according to Eschweiler-Clark and debromination. In thisprocess, it has not been possible to detect (+/−) epigalanthamine in thereaction product by chromatographic methods. Galanthamine andgalanthamine derivatives can be prepared on an industrial scale by theprocess according to the invention via intermediates which are notdescribed in the literature (see the compounds mentioned in claims 64 to67).

The processes of the present invention, which are considerably improvedwith respect to yield and purity of the resulting products compared withthe prior art and can be carried out on an industrial scale, can bedescribed by way of example as follows:

For synthesis of derivatives of4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef] [2]benzazepine, of thegeneral formula (I)

or of salts thereof, wherein R₂, R₄, X₁, X₂, Y₁ and Y₂ are eitheridentical or different and are hydrogen, fluorine, chlorine, bromine,iodine, a hydroxyl or alkoxy group, a lower, optionally branched andoptionally substituted alkyl group, a lower, optionally branched alkenegroup, a lower, optionally branched alkyne group, an optionallysubstituted aryl, aralkyl or aryloxyalkyl group, the alkyl chain ofwhich is optionally branched and the aromatic nucleus of which isoptionally substituted, a formyl group, at unbranched or branchedalkylcarbonyl, arylcarbonyl, aralkyl carbonyl, alkyloxycarbonyl,aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl orarylsulfonyl which are unsubstituted or substituted by one or morehalogens and Y₁, Y₂ can be =0 (ketone),

wherein A is a benzene nucleus, which is optionally mono- orpolysubstituted by at least one lower, optionally branched alkyl, group,at least one lower, optionally branched alkene group, at least onelower, optionally branched alkyne group, at least One lower, optionallybranched alkoxy group, by fluorine, chlorine, bromine or iodine or byseveral identical or different halogens, at least monosubstituted alkylgroup [sic], such as chloromethyl and trifluoromethyl, at least oneoptionally substituted aralkyl group, at least one hydroxyl group,primary, secondary or tertiary amino group, nitro group, nitrile group,alkylamino group or arylamino group, aldehyde group, carboxylic acidgroup and all derivatives of the carboxylic acid group, such as esters,amides and halides, a process is used comprising a condensation stepwith subsequent reduction, an N-formylation or introduction of anN-protective group, a bromination (which can also already be carried outat the stage of isovanillin in accordance with the overall equation), inoxidative cyclization, a reduction, depending on the mature of thereducing agent also additionally an N-methylation and debromination, anda separation of the optical isomers. If required, individual processsteps of those mentioned can also be omitted.

The present invention also relates to the preparation of salts of thetitle compounds.

The compounds of the general formula (I) can be converted into saltswith organic and inorganic acids, for example:

of mineral acids, such as hydrochloric and hydrobromic acid, sulfuricacid and phosphoric acid, and perchloric acid, or pharmaceuticallyacceptable Organic acids, such as lactic acid, substituted andunsubstituted tartaric acid, acetic acid, salicylic acid, citric acid,benzoic acid, β-naphthoic acid, adipic acid and the like.

The processes of the invention in some cases lead to new compounds. Thenew compounds include:

bromogalanthamine of the formula

epibromogalanthamine of the formula

N-demethylbromogalanthamine of the formula

and

N-demethyl-epibromogalanthamine of the formula

The invention also relates to the preparation of salts of thesubstituted derivatives of4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef]benzazepine, of thegeneral formula (II)

in which R₂, R₄, X₁, X₂, Y₁ and Y₂ and A have the meanings given abovefor formula (I) and Z⁻ is an organic anion of a pharmaceutically usefulacid, such as tartrate, lactate, citrate, acetate, maleate and the like,or an inorganic anion, such an a fluorine, chlorine, bromine or iodineanion, or a sulfate or phosphonate or chlorate anion, R₅ is a hydrogenatom, a lower, unbranched or branched alkyl radical, aryl or an aralkylradical which is branched or unbranched in the alkyl chain, by theprocess described above by way of example.

The compounds obtainable according to the invention and salts thereofcontain at least two asymmetric cantors and therefore occur in severalstereoisomeric forms. The invention also relates to the separation ofthe resulting diastereomers or racemates into the optically putsantipodes and mixtures thereof.

The abovementioned steps can be carried out generally and by way ofexample an follows:

1. Condensation and reduction

To prepare the compounds of the general formulae (I) and (II),substituted derivatives of the general formula (V) where R₄=H areprepared by a procedure in which a compound of the general formula (III)wherein R₁ and R₂ are hydrogen, a lower, unbranched or branched alkyl oran aryl or aralkyl which in branched or unbranched in the alkyl chain,as well as alkyl-carbonyl, aryl-carbonyl and aralkylcarbonyl, ortogether (R₁=R₂=—CH₂—) an alkyl group or a combination of theseradicals, X₁=H, fluorine, chlorine, bromine, iodine or t-butyl issubjected to a condensation reaction with tyramine or substitutedtyramine (R₃=hydrogen, a lower unbranched or branched alkyl, aryl or anaralkyl which is branched or unbranched in the alkyl chain, as well asalkylcarbonyl, arylcarbonyl, and aralkylcarbonyl). The procedure herecan be as follows:

An equimolar solution of (III) and (IV) in toluene, xylene or benzene ormixtures of these solvents with higher alcohols, chiefly toluene withn-butanol, in ratios of 9:1 to 1:9, chiefly 1:1, in concentrations of1-30%, is reacted at the reflux temperature and water is separated off.The solvent is then separated off by distillation and recovered to theextent of >95%, and the is dissolved in alcohol, such as methanol,ethanol, n-propanol, i-propanol, methylglycol or ethylglycol, water,glacial acetic acid or mixtures of these solvents, chiefly methanol, inconcentrations of 1-30% and reduced by addition in portions of 0.6 to 5equivalents, preferably 0.65 to 0.7 equivalent, of reducing agents, suchas sodium borohydride, potassium borohydride, sodium cyanoborohydrideand LiAlH₄, and mixtures of these, but chiefly sodium borohydride, inpowder or granule form, at a temperature from −30° C. up to the refluxtemperature. The condensation product (V) is filtered off from thealcoholic solution as the first fraction by filtration in yields of 80to 85%. Working up of the alcoholic solution by distillation to 15 to30% of the volume and filtration of the 2nd fraction increases the yieldto 90 to 95% of theory. Alternatively, the reaction solution can bepoured onto water, whereupon crystalline product (V) precipitates outand, after filtration with suction and drying, is obtained in yields ofup to 95%.

2. N-Formylation or N-protective group:

Starting compounds for the oxidative cyclization of the formula (V)where R₄=formyl or unbranched or branched aralkyl, alkylcarbonyl,arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl,aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl or arylsulfonyl whichare unsubstituted or substituted by one or more halogens are prepared byreaction of the compounds (V) where R₄═H with the corresponding acids,esters, anhydrides, halides, azides, carbonates or other reactivederivatives of these protective groups.

In particular, a compound of the general formula (V) where R₄═H can bereacted in solvents such as THF, dioxane, DMF, toluene, xylene ormixtures of these solvents with the equimolar to 50 times the molaramount of the ethyl formate and catalytic amounts of formic acid (0.001to 1 equivalent) at a temperature from 0° C. to the reflux temperatureto give a compound of the general formula (V) where R₄═CHO. The solventsare removed in this process by vacuum distillation, the distillationresidue crystallizes by addition in portions of water and ice and theproduct is obtained in yields of >90% at a content of >95% byfiltration.

3. Bromination:

If, in compounds of the general formula (V) where R₁, R₂, R₃=a lowerunbranched or branched alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonylor aralkylcarbonyl, X₁, X₂═H, R₄=formyl, or unbranched or branchedaralkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl,aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl orarylsulfonyl which are unsubstituted or substituted by one or morehalogens, with a content of 90 to 100% in solvent mixtures ofhalogenated hydrocarbons, such as chloroform or methylene chloride, withalcohols (methanol, ethanol, methylglycol, ethylglycol, ethylene glycol,n-propanol, i-propanol) in ratios of 9:1 to 1:9, preferably 3:2 to 2:3,and of pure alcohols (methanol, ethanol, methylglycol, ethylglycol,ethylene glycol, n-propanol, i-propanol) and mixtures thereof with oneanother, preferably ethanol/methylglycol, in ratios of 9:1 to 1:9,preferably 3:2 to 2:3, with water contents of 0 to 5%, preferably 0 to0.2%, at a temperature of −80 to +60° C., preferably −40 to 0° C., in aconcentration of 0.5 g to 20 g/100 ml of solvent, the reaction iscarried out with 1.0 to 3.0, preferably 1.4 to 1.7 equivalents of abromine reagent which is obtained by addition of elemental bromine intothe solvents mentioned in a concentration of 1 to 90%, preferably 2 to10%, with addition times of the bromine reagent of 10 minutes to 4hours, preferably 15 to 30 minutes, the compound of the formula (V)where X₁═Br is obtained in yields of 90 to 96% of theory after areaction time of 0.5 to 24 hours, preferably 30 to 60 minutes, and afterworking up (concentration by distillation to 10 to 25% of the volume andpouring onto 10 to 50 times the amount of ice-water, filtration anddrying).

Preparation of the intermediate (V) where X₁═Br, R₄═CHO orpolybrominated intermediate:

Route 1 (see page 24, overall equation): if a compound of the formula(V) where X₁, X₂═H and R₄═CHO is brominated in accordance with theworking instructions given, for example, 82% of product, 6% ofprecursor, 8% of by-product where X₂═Br and 5% of more highly brominatedproducts are obtained. (HPLC, Lichrosorb RP 18, 5μ, 300/4 mm, eluantMeOH/H₂O 6:4 at 280 nm). If the bromination method is changed, theratios of the products stated also change (a higher content of morehighly brominated products is usually formed). After the oxidativecyclization, in addition to the desired compound of the general formula(I) where X₁═Br, R₄═CHO and Y₁═Y₂═O, [lacuna] could be detected in theprecursor in contents corresponding to the content of the compound ofthe general formula (V) where X₁═X₂═Br, R₄═CHO (HPLC, Lichrosorb Si 60,10μ, 300/4 mm, eluant: CHCl₃/MeOH 95:5 at 254 nm) and isolated by meansof preparative chromatography (silica gel 60, CHCl₃:MeOH 1-5%). Afterreduction with L-Selektride or with other reducing agents, more highlybrominated narwedine (X₁═X₂═Br) is either likewise reduced togalanthamine or separated off by preparative chromatography.

Route 2: (see page 24, overall equation). Starting fromveratrumaldehyde, via 6-bromo-isovanillin, the compound of the formula(V) where X₁═Br, R₄═CHO can be prepared by condensation andN-formylation without more highly brominated by-products.

4. Oxidative cyclization:

For oxidative cyclization of compounds of the general formula (V) whereR₂=hydrogen, a lower, branched or unbranched alkyl, aryl, or an aralkylwhich is branched or unbranched in the alkyl chain, or alkyl-carbonyl,arylcarbonyl and aralkyl-carbonyl or a combination of these radicalsX₁═H, fluorine, chlorine, bromine, iodine or t-butyl, R₄=formyl, orunbranched or branched aralkyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstitutedor substituted by one or more halogens, R₃=hydrogen, to give a compoundof the general formula (I) where R₂, R₄, X₁ are as above, Y₁, Y₂═O(ketone) and X₂═H or Br, the reaction is carried out in solvents, suchas chloroform, methylene chloride, ethyl acetate, THF, dioxane, glacialacetic acid, water, mixtures thereof with alcohols (methanol, ethanol,methylglycol, ethylglycol, ethylene glycol, n-propanol, i-propanol) inratios of 9:1 to 1:9, and also toluene, xylene or benzene, chieflyxylene and toluene, in a concentration of 0.05 g to 10 g/100 ml ofsolvent, with bases, such as sodium hydrogencarbonate, potassiumcarbonate, NaOH, KOH or pyridine, preferably potassium carbonate, in aconcentration of 0.1% to a saturated solution or suspension, chiefly 5to 20%, and oxidizing agents, such as Pb(OAc)₄, KMnO₄, FeCl₃, potassiumferricyanide of H₂O₂, preferably potassium ferricyanide, 4-10equivalents, preferably 5.5-6 equivalents, if necessary with addition ofphase transfer catalysts, such as Aliquat or crown ethers, as well asascorbic acid, CuCl or trifluoroacetic acid, at a temperature from −40°C. to the reflux temperature, chiefly 50 to 80° C., and by rapidaddition or addition in portions of the precursor as a solid, as asolution or as a suspension in a solvent, preferably as a solid, with areaction time of 10 minutes to 72 hours, chiefly 15 to 45 minutes, withvigorous mechanical stirring, preferably using a stirrer and ahomogenizer, if necessary under an inert gas, such as N₂, CO₂ or argon,chiefly argon. Working up by filtration, phase separation and vacuumdistillation of the toluene phase gives the crude product in yields of 5to 65%, from which yields of 5 to 50% are obtained by purification ofthe cyclization products.

5. Reduction:

For reduction of compounds of the general formula (I) in which R₂ is alower unbranched or branched alkyl, aryl, aralkyl, alkylcarbonyl,arylcarbonyl or aralkylcarbonyl, X₁, X₂ are fluorine, chlorine, bromine,iodine or t-butyl, R₄ is formyl, or unbranched or branched aralkyl,alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkyloxycarbonyl,aryloxycarbonyl, aralkyloxycarbonyl, alkylsulfonyl, aralkylsulfonyl orarylsulfonyl which are unsubstituted or substituted by one or morehalogens and Y₁, Y₂═O (bromonarwedine type), with hydride reagents, suchas DiBAl—H, DiBAl—H/ZnCl₂, Al isopropylate, Red-Al, K-Selektride,L-Selektride, KS-Selektride, LS-Selektride, Li-tri-t-butoxy-AlH,Li-tri-ethoxy-AlH, 9-BBN, Superhydride, NaBH₄, Zn(BH₄)₂, AlH₃, AlCl₂H ora combination of these reducing agents, a procedure can be followed inwhich the reduction is carried out by addition of the reducing agent inequimolar amounts or in excess to the starting substance or inverseaddition of the starting substance to the reducing agent in an inertsolvent, such as diethyl ether, THF, dioxane, toluene, xylene orbenzene, at temperatures from −50° C. to the reflux temperature. Afteralkaline (chiefly NH₄OH) or acid (chiefly 2N HCl) working up andsubsequent extraction with solvents such as toluene, xylene, benzene,ethyl acetate, ether, chloroform or methylene chloride, the crudeproduct is purified by chromatographic processes and, as required, thediastereomers are isolated or the crude products are reacted furtherdirectly.

In particular, N-demethylbromogalanthamine is obtaineddiastereoselectively in yields of 70-85% of theory, after purificationby column chromatography, by reduction of bromo-N-formylnarwedine (incontrast to Lit. 24, where narwedine is used) with L-Selektride orK-Selektride. No epi-N-demethylbromogalanthamine could be detected bychromatographic methods.

N-demethylbromogalanthamine is converted into bromogalanthamine inyields of 80-90% of theory by N-methylation, for example by boiling upfor 10 minutes to several hours in a 5- to 50-fold excess of formic acidand aqueous formaldehyde solution.

Bromogalanthamine is converted into galanthamine, for example, byheating at the reflux temperature with a 5- to 50-fold molar excess offormic acid and triethylamine in the presence of 0.1 to 15% ofpalladium/active charcoal catalyst for 1 to 12 hours, bromine beingeliminated. Yield: 70 to 80% of theory.

The reaction stages can also be carried out without isolation andpurification of the intermediates.

A mixture of N-demethylbromogalanthamine andepi-N-demethylbromogalanthamine in a ratio of about 1:1 is obtained byreduction of the precursor with Li-tri-t-butoxy-AlH.

Reduction with DiBAl—H gives 43% of bromogalanthamine and 41% ofepibromogalanthamine.

Reduction with Li—AlH₄/anhydrous H₂SO₄ also gives bromogalanthamine andepibromogalanthamine in a ratio of about 3:1.

The reduction can be carried out, for example, as described below:

For reduction of a compound of the general formula (I) with R₂=alkyl,X₁═Br, R₄═CHO, X₂═H, Y₁, Y₂═O (ketone), the precursor is dissolved in asolvent such as THF, dioxane or other ethers, chiefly THF, inconcentrations of 0.1 to 20 g/100 ml by heating. 3 to 5, chiefly 3.5equivalents of L-Selektride, chiefly as a 1 molar solution in THF, arethen added at a temperature of from −50° C. to the reflux temperature,chiefly at 0-20° C., and the mixture is reacted by stirring for 20minutes to 48 hours, chiefly one hour. The complex formed with thereducing agent is destroyed by addition of water and ammonium hydroxideand excess organic solvent is evaporated off in vacuum by heating to notmore than 30° C. Extraction with solvents such as ethers (e.g. diethylether), ethyl acetate, butyl acetate, chloroform, methylene chloride,toluene, benzene or xylene gives N-demethylbromogalanthamine in crudeyields of 90 to 100% of theory.

For monomethylation of N-demethylbromogalanthamine, a solution ofN-demethylbromogalanthamine in a 5- to 30-fold molar excess of formicacid and aqueous formaldehyde solution (37%) is heated at the refluxtemperature, with or without an organic solvent, for 10 minutes to 2hours, chiefly 15 to 20 minutes.

For debromination of bromogalanthamine or epibromogalanthamine, bromo-or epibromogalanthamine is heated at the reflux temperature in a 5- to50-fold molar excess of formic acid and triethylamine, with or withoutan organic solvent, in the presence of 0.1 to 15% of palladium/activecharcoal catalyst for 1 to 12 hours, chiefly 2.5 hours.

For reduction of a compound of the general formula (I) where R₂=alkyl,X₁═Br, R₄═CHO, X₂═H, Y₁, Y₂═O (ketone), the precursor is suspended in aninert organic solvent, such as benzene, toluene or xylene, chieflytoluene, in a concentration of 0.1 to 20 g/100 ml, and 3 to 5, chiefly3.5 equivalents, of DiBAl—H, as a chiefly 1.5 molar solution in toluene,are added dropwise at a temperature from −50° C. to reflux temperature,chiefly 0 to 20° C. The mixture is then stirred at this temperature for20 minutes to 12 hours, chiefly 30 minutes to 1.5 hours, the complexformed is destroyed with water and ammonium hydroxide, the mixture isextracted with toluene and the crude product (90 to 100% of theory) isseparated into 43% of bromogalanthamine and 41% of epibromogalanthamineby means of column chromatography (silica gel, acetone/hexane 1:1).

6. Separation of optical isomers:

To separate chiral 4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef] [2]benzazepines of the general formula (I), (Y₁═H, OH; Y₂═, OH) in which A,R₂, R₄, X₁ and X₂ have the abovementioned meanings, into theenantiomerically pure antipodes, the method of fractionalcrystallization of salts with chiral acids can be used. The separationof the (+) and (−) isomers of the compounds of the narwedine type(compounds of the general formula (I) in which Y₁ and Y₂ together are ═O(ketone)) by fractional crystallization is carried out by a procedure inwhich a solution or suspension of the optical isomer mixture in 5 to 50times the amount of a solvent, such as water, methanol, ethanol,propanol, isopropanol, acetone or mixtures of these solvents, chieflymethanol, is combined with the equimolar amount or an excess of a chiralacid (unsubstituted or mono- or polysubstituted + or − tartaric acid,citric acid, lactic acid, α-methoxyphenylacetic acid, camphorsulfonicacid and derivatives thereof, preferably di-p-tolyl (+) tartaric acid),which is dissolved in one of the abovementioned solvents, the solutionis seeded with crystals prepared from naturally occurring (−)galanthamine derivatives and chiral organic acids, such as di-p-tolyl(+) tartaric acid, and left to stand at −40 to +20° C., preferably 0°C., for 2 to 24 hours or longer, and the crystals formed are filteredoff and dried, excess NH₄OH is then added, the mixture is extracted withorganic solvents, such as chloroform, methylene chloride, ethyl acetate,butyl acetate, diethyl ether, t-butyl methyl ether, dibutyl ether,petroleum ether, xylene, benzene, toluene or similar solvents, and thecorresponding (−) galanthamine derivative is isolated by distillation ofthe solvent.

In this process, concentration of the mother liquor, taking up in excessNH₄OH, extraction with an organic solvent (as mentioned above) andevaporation gives further fractions of galanthamine, from which the (+)galanthamine derivatives can be obtained in a manner analogous to thatabove with the aid of the chiral organic acids, such as, for example,di-p-tolyl (−) tartaric acid.

The products obtained according to the invention can be purified by aprocess customary in chemistry, for example fractional distillation,crystallization or chromatography.

W. C. Shieh and J. A. Carlson report in J. Org. Chem. 1994, 59,5463-5465 the (−)galanthamine is a selective acetylcholinesteraseinhibitor which strengthens the cholinergic function and is consideredas a product for treating individuals suffering from Alzheimer'sdisease.

In order to prepare enantiomerically pure (−)galanthamine it is proposedto add catalytic amounts of (−)narwedine seed crystals or(+)-galanthamine seed crystals to (±)narwedine in solution and to allowcrystallization to take place. In this procedure, (−)narwedinecrystallizes out in the form of white crystals from the solutioncontaining (±)narwedine. To convert (−)narwedine to (−)galanthamine byreduction, a diastereoselective reduction of enantiomerically purenarwedine is proposed. (−)Narwedine obtained by the diastereoselectivecrystallization is reduced stereospecifically by means of L-Selektrideto (−)galanthamine in a yield of almost 99% at −78° C. For the two-stageprocess (crystallization and reduction), overall yields in theconversion of racemic narwedine to (−)galanthamine of 90% are quoted.With regard to the preparation of (±)narwedine reference is made to Lit.23 (Holton et al.), a method in which stoichiometric amounts ofpalladium and thallium are required.

One of the disadvantages of the process described is that the reductionhas to be carried out under the described process conditions at −78° C.Furthermore, only a semi-microbatch (285 mg of precursor) is described,which is carried out in about 200 times the amount of solvent and isworked up chromatographically using CH₂Cl₂/methanol (6:1).

Reaction equations of the processes according to the invention are shownbelow.

Overall Reaction Equation

Reductions of Bromonarwedine—Overview

Reduction with L-Selektride

Chiral Separation of Galanthamine

According to one variant of the process of the invention, narwedine canbe obtained starting from the cyclized compound of the general formula(I) where Y₁, Y₂=O (ketone) via the introduction of a cyclic ketal as aprotective group (Y₁, Y₂=substituted or unsubstituted cyclic ketal orthioketal, for example propylene glycol; O—CH₂—CH₂(CH₃)—O), subsequentreduction with LiAlH₄ and splitting off of the ketal protective group.Racemic narwedine (or a compound of the general formula (I) in which Y₁,Y₂ are ═O (ketone)) can be enriched by addition of catalytic amounts of(+)galanthamine or of (−)narwedine and (−)narwedine can be obtained withan enantiomeric purity of >98%.

The advantage of this variant of the invention is that the unwantedenantiomer can be converted into the desired enantiomer.

Racemic narwedine can be enriched to (+)narwedine in a similar manner byaddition of catalytic amounts of (−)galanthamine or (+)narwedine.Enriched narwedine is converted into enantiomerically pure galanthaminein a good yield with L-Selektride, it being possible for either the freebase or, directly, the hydrobromide to be obtained by appropriateworking up. Galanthamine hydrobromide can be obtained with anenantiomeric content of >99% by crystallization of the hydrobromide. Thecontent is determined by measurement of the optical rotation and byquantitative determination of the enantiomers by means of microcapillaryelectrophoresis in chiral electrolyte.

The abovementioned steps can be carried out generally and by way ofexample as follows:

7. Introduction of the protective group:

For introduction of a ketal protective group the compound of the generalformula (I) where Y₁, Y₂ are ═O (ketone), X₁ is Br and R₁ is CHO isheated at the reflux temperature in solvents, such as benzene, tolueneor xylene, but chiefly toluene, together with 1 to 30 times the amountof diols, such as ethylene glycol or propylene glycol, or dithiols, suchas 1,3-dithiopropane, in the presence of catalytic amounts ofp-toluenesulfonic acid or concentrated sulfuric acid or other acids forseveral hours using a water separator. The mixture is subsequentlycooled and the diol phase (dithiol phase) is separated off and extractedwith toluene and the ketal (thioketal) obtained is isolated byevaporation of the toluene phases.

8. Reduction, splitting off of the protective group:

Purified or crude ketal (thioketal) of the general formula (I) (chieflywhere X₁ is Br and R₄ is CHO) is converted into narwedine by reductionwith LiAlH₄ and subsequent splitting off of the ketal group. Forexample, the propylene glycol ketal of the compound of the generalformula (I) is dissolved in THF, 3 to 5 times the stoichiometric amountof LiAlH₄ are added and the mixture is heated at the reflux temperaturefor 12 hours. Any X₁Br is thereby also converted into X₁H and R₄CHO isconverted into R₄CH₃. Decomposition of the excess LiAlH₄ with NH₄OH,filtration and extraction with EtOAc gives the ketal-protected compoundof the general formula (I) of the narwedine type. Heating the crudeproduct in an acid, chiefly 2N hydrochloric acid, and rendering themixture alkaline with NH₄OH gives the compound of the general formula(I) of the narwedine type in a good yield (about 80%). If the mixture isstirred with LiAlH₄ at −10° to 0° C. for 2 hours and then hydrolyzedwith NH₄OH and extracted with EtOAc, ketal-protectedN-demethylbromonarwedine can be obtained. In a manner comparable to thatof reduction with L-Selektride, a compound of the general formula (I)where R₄ is CH₂—OH is intermediately formed, and is decomposed duringthe hydrolysis to give the N-demethyl compound. By treatment in 2N HClthe ketal group can be split off and a compound of thedemethyl-bromo-narwedine type can be obtained. Alkylation of theO-protected or unprotected compounds of the demethyl-bromo-narwedinetype or introduction of an N-protective group and splitting off of anyO-protective group present gives differently substituted narwedine ofthe general formula (I) where Y₁, Y₂=O (ketone), and where R₄ issubstituted or unsubstituted alkyl, alkenyl, alkynyl, aryl or aralkyl orany protective group or quaternized compounds of the general formula(II). Debromination, for example with Zn/CaCl₂, gives N-substitutedcompounds of the narwedine type.

If a compound of the general formula (I) where Y₁, Y₂=ethylene glycolketal is heated at 45-50° C. with LiAlH₄ in THF for 12 hours,correspondingly ketal-protected narwedine is formed. If the pressure isheated at the reflux temperature (65-68° C.) for 24 hours, the cyclicketal structure opens up and a product where Y₁ is —CH₂—CH₂—OH and Y₂ isH is formed, but this can likewise be converted into a compound of thenarwedine type by brief heating in an acid, chiefly 2N HCl.

It is interesting that the reduction with LiAlH₄ leads todemethyl-bromo-narwedine ketal at 0° C., to narwedine ketal at 45° C.,to galanthamine hydroxyethyl ether at 70° C. over 48 hours and tonarwedine at 45-70° C. with subsequent treatment with HCl (also splitsthe ketal).

Reduction of a ketal-protected compound of the general formula (I) whereX₁ is Br and R₄ is CHO with Zn/CaCl₂ leads to reduction of the bromide,to splitting off to the ketal group but to retention of R₄ CHO.

9. Enrichment:

A racemic compound of the general formula (I) where Y₁, Y₂=O (ketone),R₄ is CH₃ is heated at the reflux temperature in a solvent such aswater, methanol, ethanol, n-propanol, butanol, methylene glycol,ethylene glycol or mixtures of these solvents with 1 to 30% oftriethylamine or similar bases, and optically pure compounds, forexample (+)galanthamine or (−)narwedine, are added. For example, either(+)galanthamine or (−)narwedine are used for (−)narwedine, and for(+)narwedine, for example, (−)galanthamine or (+)narwedine are used andthe mixture is cooled slowly in stages.

The mixture is preferably stirred at 40° C. for 1 to 14 days and thencooled to 0-20° C., and the optically enriched crystals which haveprecipitated out are isolated and an enantiomeric content of >98% isdetermined by means of microcapillary electrophoresis. Optical rotationsof 405-407° C. (20° C., c=1/CHCl₃), for example, are achieved here fornarwedine. Determination by means of microcapillary electrophoresis inchiral electrolytes gives an enantiomeric content of >98%.

10. Reduction:

The enantiomerically pure compound of the narwedine type (Y₁, Y₂=O,ketone) can be converted diastereoselectively into the enantiomericallypure compound of the galanthamine type (Y₁ or Y₂ is OH) withL-Selektride analogously to the instructions already given. Working upwith aqueous HBr gives the corresponding galanthamine hydrobromide withan enantiomeric content of >99%, in a yield of 87-95% of theory.

11. Splitting off of bromide:

A compound of the general formula (I) where X₁ is Br is dissolved in 5to 50 times the amount of a solvent, such as water, methanol, ethanol,n-propanol, iso-propanol, n-butanol or mixtures thereof, chiefly 70% ofethanol, 1 to 5 times the amount of zinc powder and 1 to 10 times theamount of CaCl₂ are added and the mixture is stirred. After on averageabout 1 to 2 hours, the solid is filtered off and the solutionevaporated and chromatographed (silica gel 60, solvent for exampleacetone) to give 80 to 85% of debrominated product.

Compared with the method described in Lit. 24, it has been possible toimprove the process such that a procedure on an industrial scale ispossible. For example, the precursor is added in powder form to apreferably 1 molar solution of L-Selektride in THF at room temperature,the mixture is stirred for one hour, methanol is added and the mixtureis evaporated. Taking up in ethanol (for example 5-30 times the amount)and acidification with aqueous KBr gives galanthamine hydrobromide inyields of 90 to 95% at an enantiomeric content of >99%.

The process variant described leads in some cases to novel compounds, ornovel compounds are formed as intermediates. The novel compounds are:

Bromo-N-formyl-narwedine propylene glycol ketal (5)

Narwedine propylene glycol ketal (6)

Bromo-N-formyl-narwedine ethylene glycol ketal (7)

Narwedine ethylene glycol ketal (8)

O-(2-Hydroxyethyl)galanthamine (9)

Bromo-N-demethyl-narwedine ethylene glycol ketal (10)

Bromo-N-benzyl-narwedine ethylene glycol ketal (11)

Bromo-N-demethylnarwedine (12)

The numbers assigned to these compounds are also used in the reactionequations reproduced below.

Reaction Equations for Narwedine via Ketal-protectedBromoformylnarwedine

Overall Overview of a Preferred Process of the Invention for theSynthesis of (−)galanthamine

According to a further variant of the invention, the procedure used forpreparing racemic compounds of the narwedine type is such that acompound of the general formula (Ia)

in which R₂, R₄, X₁ and X₂ have the meanings given in connection withthe general formula (I), Z₁ and Z₂=O, S or N and Y₁ and Y₂ are ═O(ketone) is prepared by oxidative cyclization of a compound of thegeneral formula (Va)

in which R₁, R₂, R₃, R₄, X₁ and X₂ have the meanings given in connectionwith the general formula (V) and Z₁ and Z₂ are ═O, S or N.

The product is subsequently converted, for example in a manner similarto stage 7.) described above, into a ketal or thioketal or cyclic ketalor cyclic thioketal, reduced with a reducing agent such as LiAlH₄similar to stage 8.) described above, isolated as ketal or thioketal, orconverted by preferably acidic hydrolysis into the correspondingcompound of the narwedine type. The equation is given in the review“Synthese von Narwedin über Benzazepinion-Typ” (for: Z₂=H₂).

A by-product which can be formed in various concentrations as a resultof alcoholysis is a compound of the formula (VI)

in which R₂, R₄, X₁, X₂, Z₁ and Z₂ have the meanings stated inconnection with the general formula (Ia) and R₇ corresponds to thealcohol or thiol used for preparing the ketal, for example—O—CH₂CH(CH₃)—OH (propylene glycol radical).

Synthesis of Narwedine by Way of Benzazepinone Type

The reduction of the compound of the general formula (Ia) in which R₂,R₄, X₁ and X₂ have the definitions given in connection with the generalformula (I), Z₁ and Z₂=O, S, or N, and Y₁ and Y₂ are ═O (ketone) withL-Selektride gives a compound of the formula (Ia) where Y₁=OH, Y₂=H.

The reduction of a compound of the formula (Ia) where Y₁, Y₂=O withLiAlH₄ gives a mixture of the galanthamine type (Y₁=OH, Y₂=H) andepigalanthamine type (Y₁=H, Y₂=OH) in a ratio of about 5:3, where X₁,X₂=Br are reduced to X₁, X₂=H and Z═O is reduced to Z═H₂.

The described process variant leads in part to novel compounds:

Examples of the processes of the invention are given below:

EXAMPLE 1

N-(4-hydroxyphenethyl)-(3-hydroxy-4-methoxy)benzylamine

(general formula (V) where: R₁=R₃=R₄=X₁=X₂=H, R₂=Me)

217.5 g (1.43 mol) of isovanillin and 200 g (1.45 mol) of tyramine aresuspended in 2.5 l of toluene/n-butanol (1:1) in a glass 5 ldouble-walled vessel and the suspension is heated to the refluxtemperature, water being separated off. After 4 hours, the solvent isdistilled off in vacuo, the residue is taken up in 2.5 l of methanol,and 25 g of NaBH₄ (0.66 mol) are added to the clear solution. Thereaction mixture is stirred at 0° C. for 4 hours and the precipitatewhich has separated out is filtered off, washed with methanol and dried.

Yield: 332.3 g (85/1%)

Melting point: 176-178° C.

Molecular weight: C₁₆H₁₉NO₃: 273.32

EXAMPLE 2

N-(4-hydroxyphenethyl)-(6-bromo-3,4-dimethoxy)benzylamine

(general formula (V) where R₃=R₄=X₂=H, R₁=R₂=Me, X₁=Br)

2.45 g (10 mmol) of 6-bromo-3,4-dimethoxybenzaldehyde, 1.37 g (10 mmol)of tyramine in 50 ml of toluene/n-butanol (1:1) are suspended in a 100ml round-bottomed flask and the suspension is heated to the refluxtemperature, water being separated off. After 3 hours, the solvent isdistilled off in vacuo, the residue is taken up in 50 ml of methanol and0.8 g of NaBH₄ is added to the clear solution. The reaction mixture isstirred at 0° C. for 4 hours, the solvents are distilled off in vacuo,the residue is taken up in 100 ml of CH₂Cl₂ and the organic phase iswashed with twice 10 ml of water. The organic phase is dried over Na₂SO₄and filtered and the solvent is removed in vacuo. The residue whichremains is chromatographed over 150 g of silica gel with hexane:ethylacetate=2:8.

Yield: 2.95 g (80.6%) of viscous oil

Molecular weight: C₁₇H₂₀BrNO₃: 366.23

EXAMPLE 3

N-(4-hydroxyphenethyl)-(4-methoxy-3-methoxymethoxy)benzylamine

(general formula (V) where R₁=MeOCH₂O, R₂=Me, X₁=X₂=X₃=X₄=R₃=R₄=H)

0.83 g (4.2 mmol) of 4-methoxy-3-methoxymethoxy-benzaldehyde [Lit.16-17] and 0.55 g (4.0 mmol) of tyramine are suspended in 50 ml oftoluene/n-butanol (1:1) in a 100 ml round-bottomed flask and thesuspension is heated at the reflux temperature, water being separatedoff. After 4 hours, the solvent is distilled off in vacuo, the residueis taken up in 50 ml of methanol, and 0.35 g of NaBH₄ is added to theclear solution. The reaction mixture is stirred at 0° C. for 4 hours,the solvents are distilled off in vacuo, the residue is taken up in 100ml of CH₂Cl₂ and the organic phase is washed with twice 10 ml of water.The organic phase is dried over Na₂SO₄ and filtered and the solvent isremoved in vacuo. The residue which remains is chromatographed over 65 gof silica gel with ethyl acetate:methanol=7:3.

Yield: 1.12 g (83.4%) of viscous oil

Molecular weight: C₁₈H₂₃NO₄:317.37

EXAMPLE 4

N-(4-hydroxyphenethyl)-(6-bromo-3-hydroxy-4-methoxy)benzylamine

(general formula (V) where R₁=R₃=R₄=H, X₂=H, R₂=Me, X₁=Br)

Method 1:

1.0 g (4.3 mmol) of 6-bromo-4-methoxy-3-hydroxy-benzaldehyde [Lit. 18]and 0.6 g (4.3 mmol) of tyramine are suspended in 20 ml oftoluene/n-butanol (1:1) in a 50 ml round-bottomed flask and thesuspension is heated at the reflux temperature, water being separatedoff. After 90 minutes, the solvent is distilled off in vacuo, theresidue is taken up in 20 ml of methanol, and 0.33 g of NaBH₄ is addedto the clear solution. The reaction mixture is stirred at 0° C. for 4hours, the solvents are distilled off in vacuo, the residue is taken upin 50 ml of CH₂Cl₂ and the organic phase is washed with twice 10 ml ofwater. The organic phase is dried over Na₂SO₄ and filtered and thesolvent is removed in vacuo. The residue which remains ischromatographed over 60 g of silica gel with ethylacetate:methanol=97:3→95:5

Yield: 1.43 g (93.8%)

Method 2:

53.38 g (231 mmol) of 6-bromo-4-methoxy-3-hydroxybenzaldehyde [Lit. 18]and 31.7 g (231 mmol) of tyramine are suspended in 530 ml oftoluene/n-butanol (1:1) in a 1 1 round-bottomed flask and the suspensionis heated at the reflux temperature, water being separated off. After 90minutes, the solvent is distilled off in vacuo, the residue is taken upin 350 ml of methanol, and 12 g of NaBH₄ are added to the suspension.The reaction mixture is stirred at 0° C. for 1 hour and added dropwiseto 3 1 of ice-water. After the mixture has been stirred for 30 minutes,the product which has precipitated out is filtered off, washed twicewith water and dried in a vacuum drying cabinet at 60° C.

Yield: 70.2 g (86.3%)

Melting point: 122-125° C.

Molecular weight: C₁₆H₁₈BrNO_(3:)352.21

IR/KBr: 655.76 w; 800.45 m, 824.97 m; 1022.56 m; 1165.88 m; 1245.88 s;1409.83 s; 1448.40 s; 1510.79 s; 1554.48 s; 3200-3370 br.

¹H-NMR (DMSO-d₆): 7.0-6.60 (m, 6 H); 6.73 (m, 2H); 3.77 (s, 3H);2.75-2.58 (m, 4H); 2.88 (s, 2 OH). ¹³C-NMR (CDCl₃+DMSO-d₆): 155.46 s,147.28 s, 145.95 s, 130.56 s, 129.68 s, 129.12 2 d, 116.93 d, 115.61 d,114.99 2 d, 110.95 s, 55.85 q, 51.76 t, 50.16 t, 34.50 t.

EXAMPLE 5

N-(4-hydroxyphenethyl)-(4methoxy-3-t-butyl-carbonyloxy)benzylamine

(general formula (V) where R₁mMe₃CCO, R₂=Me, X₁=X₂=R₃=R₄=H)

3.63 g (16.5 mmol) of (4-methoxy-3-t-butyl-carbonyloxy)benzaldehyde and2.06 g (15 mmol) of tyramine are suspended in 32 ml oftoulene/n-butanol=1:1 in a 50 ml round-bottomed flask and the suspensionis heated at the reflux temperature, water being separated off. After 3hours, the solvent is distilled off in vacuo, the residue is taken up in32 ml of methanol, and 1.32 g of NaBH₄ are added to the clear solution.The reaction mixture is stirred at 0° C. for 4 hours, the solvents aredistilled off in vacuo, the residue is taken up in 50 ml of CH₂Cl₂ andthe organic phase is washed with twice 10 ml of water. The organic phaseis dried over Na₂SO₄ and filtered and the solvent is removed in vacuo.The residue which remains is chromatographed over 140 g of silica gelwith ethyl acetate:methanol=9:1→8:2.

Yield: 1.7 g (28.8%) of viscous oil

Molecular weight: C₂₁H₂₇NO₄:357.43

EXAMPLE 6

N-formyl-N-(4-hydroxyphenethyl)-(3-hydroxy-4-methoxy)benxylamine

(general formula (V) where: R₁=R₃=X₁=X₂=H, R₂=Me, R₄=CHO)

370 g (1.35 mmol) of compound 5 (R₁=R₃=R₄−X₁=X₂=H,R₂=Me), 5 1 oftechnical grade dioxane and 370 ml of technical grade DMF are initiallyintroduced into a 10 1 three-necked flask (dropping funnel, refluxcondenser, bubble counter, gas inlet tube). The dropping funnel isfilled with a mixture of 1100 ml (13.66 mol) of HCOOEt and 10 ml ofHCOOH, and the suspension is stirred magnetically under argon and heatedto the boiling point. The internal temperature rises up to 100 to 103°C., the suspension becoming homogeneous. The solution from the droppingfunnel is added to this solution in the course of 20 to 30 minutes. Theinternal temperature thereby drops to 87 to 89° C. The reaction mixture,which has become cloudy, is stirred at the reflux temperature for 4hours. The solvent is removed in vacuo and 8 1 of ice-water are added tothe residue in portions. The crystals which are precipitated out arefiltered off, washed three times with 2 1 of water and dried in vacuofor 12 hours.

Yield: 360.5 g (88.6%)

Melting point: 144 to 148° C.

Molecular weight: C₁₇H₁₉NO₄:301.33

EXAMPLE 7

N-formyl-N-(4-hydroxyphenethyl)-(6-bromo-3,4-dimethoxy)benzylamine

(general formula (V) where: R₃=X₂=H, X₁=Br, R₁=R₂=Me, R₄=CHO)

A mixture of 4.53 g (12.2 mmol) of 5 (R₃=R₄=X₂=H,X₁=Br, R₁=R₂=Me), 100ml of technical grade dioxane, 10.0 ml (122.0 mmol) of HCOOEt and 0.1 mlof HCOOH is boiled under reflux in a 250 ml three-necked flask (droppingfunnel, reflux condenser, bubble counter, gas inlet tube). After 68hours, the solvent is removed in vacuo and the residue is crystallizedfrom 40 ml of MeOH.

Yield: 3.61 g (75%)

Melting point: 160 to 162° C.

Molecular weight: C₁₈H₂₀BrNO₄:394.24

EXAMPLE 8

N-formyl-N-(4-hydroxyphenethyl)-(4-methoxy-3-t-butylcarbonyloxy)benzylamine

(general formula (V) where R₁=Me₃CCO, R₂=Me, X₁=X₂=R₃=H, R₄=CHO)

A mixture of 1.7 g (4.7 mmol) of the compound of the formula (V)R₁=Me₃CCO, R₂=Me, X₂=X₂=R₂=R₄=H), 7.5 ml of technical grade dioxane, 7.5ml of HCOOEt and one drop of HCOOH is boiled under reflux in a 500 mlthree-necked flask. After 15 hours, the solvent is removed in vacuo andthe residue is chromatographed on 30 g of SiO₂ with AcOEt.

Yield: 1.5 g (81.8%) of an oil

Molecular weight: C₂₂H₂₇NO₅:385.44

¹H-NMR (CDCl₃): 8.20 and 7.80 (2s, 1 H); 7.16-6.80 (m, 7H); 4.30 (d, 2H); 3.78 (s, 3 H; 3.35 (m, 2 H); 2.70 (m, 2 H); 1.38 (s, 9 ).

¹H-NMR (CDCl₃): 8.20 and 7.80 (2s, 1 H); 7.16-6.80 (m, 7H); 4.30 (d, 2H); 3.78 (s, 3 H); 3.35 (m, 2 H); 2.70 (m, 2 H); 1.38 (s, 9 H).

¹³C-NMR (CDCl₃): 176.69 s; 163.24 and 162.90 d; 155.36 and 154.99 s;150.99 and 150.70 s; 140.35 and 140.18 s; 129.67 to 112.30 m; 55.85 q;50.94 and 48.46 t; 44.60 and 43.61 t; 38.94 s; 33.60 and 32.24 t; 27.053 q.

EXAMPLE 9

N-formyl-N-(4-hydroxyphenethyl)-(6-bromo-3-hydroxy-4-methoxy)benzylamine

(general formula (V) where R₁=R₃=X₂=H, X₁=Br, R₂=Me, R₄=CHO)

Method 1:

A mixture of 27 g (76.6 mmol) of the compound (V) (R₁=R₃=R₄=X₂=H, X₁=Br,R₂=Me), 300 ml of technical grade dioxane, 30.0 ml (37.2 mmol) of HCOOEtand 0.1 ml of HCOOH is boiled under reflux in a 500 ml three-neckedflask (dropping funnel, reflux condenser, bubble counter, gas inlettube). After 72 hours, the solvent is removed in vacuo and the residueis crystallized from 50 ml of chloroform.

Yield: 23.95 g (82.3%)

Method 2:

300 g of the compound (V) (R₁=R₃=X₁=X₂=H, R₂=Me,R₄=CHO) were dissolvedin 2000 ml of anhydrous ethanol and 2000 ml of methylglycol (H₂O<0.1%)by heating to 40 ° C., the solution was then cooled to −20° C. and 14 mlof bromine in 1000 ml of ethanol/methylglycol (1:1) were added dropwisein the course of 15 minutes such that the temperature did not exceed−20° C. The mixture was then stirred at −20° C. for 30 minutes and thesolution was then concentrated to about 1000 ml and poured onto 30 1 ofice-water with vigorous stirring. The mixture was stirred at 0° C. for 4hours, the solid was filtered off with suction and the colorless,crystalline substance was dried in vacuo (60° C.).

Yield: 370.2 g (96% of theory); content (HPLC) 82%

Melting point: 162 to 164° C.

Molecular weight: C₁₇H₁₈BrNO₄:380.22

EXAMPLE 10

N-formyl-N-(4-hydroxyphenethyl)-(4-methoxy-3-methoxymethoxy)benzylamine

(general formula (V) where R₁=MeOCH₂O, R₂=Me, X₁=X₂=R₃=H, R₄=CHO)

A mixture of 4.9 g (15.4 mmol) of the compound (V) (R₁=MeOCH₂O, R₂=Me,X₁=X₂=R₃=R₄=H), 60 ml of HCOOEt and one drop of HCOOH is boiled underreflux in a 50 ml three-necked flask (dropping funnel, reflux condenser,bubble counter, gas inlet tube). After 18 hours, the solvent is removedin vacuo and the residue is crystallized from AcOEt/hexane.

Yield: 3.95 g (74%)

Melting point: 102 to 104° C.

Molecular weight: C₁₉H₂₃NO₅:345.38

¹H-NMR (CDCl₃): 8.23 and 7.83 (2 s, 1 H); 7.05 to 6.70 (m, 7 H); 5.20(s, 2 H); 4.46 and 4.28 (2 s, 2 H); 3.87 (s, 3 H); 3.52 (s, 3 H); 3.38(m, 2 H); 2.70 (m, 2 H).

¹³C-NMR (CDCl₃): 163.20 and 162.86 d; 155.41 and 155.05 s; 149.53 and149.30 s; 146.53 and 146.33 s; 129.66 and 129.59 s; 129.52 d; 128.56 and128.02 s; 122.40 d; 121.64 d; 116.71 d; 115.88 d; 115.60 and 115.33 d;11.75 d; 95.39 t; 56.13 q; 55.79 q; 51.44 and 48.62 t; 45.10 and 43.71t; 33.72 and 32.27 t.

EXAMPLE 11

4 a,5,9,10,11,12-hexahydro-1bromo-3-methoxy-11-formyl-6H-benzofuro [3a,3,2-ef] [2]benzazepin-6-one

(general formula (I) where: R₂=Me, R₄=CHO, X₁=Br, X₂=H, Y₁,Y₂=))

120 g (0.316 mol) of finely powdered compound (V) (R₁=R₃=X₂=H, X₁=Br,R₂=Me, R₄=CHO) are added all at once to a suspension of 16 1 of toluene,600 g of K₃[Fe(CN)₆]and 2 1 of 10% strength K₂CO₃ solution at 70° C. Thereaction mixture is then stirred intensively at the same temperature for30 minutes, with a homogenizer switched on, an insoluble polymerprecipitating out. The reaction mixture is filtered, the organic phaseis dried over Na₂SO₄ and filtered and the solvent is removed in vacuo.

Yield: 59.6 g (49.9%).

If precursor prepared according to Example 9, method 2 is employed forthe cyclization, a by-product of the general formula (I) with R₂=CH₃,X₁=X₂=Br, R₄=CHO; Y₁, Y₂=O was obtained in a 6% yield after separationby means of column chromatography (silica gel 60, CHC1 ₃/MeOH (1-5%)).

¹H-NMR (CDCl₃): 8.23 (d, 1H), 7.30 (s, 1H), 6.98 (s, 1H), 5.85-3.95 (m,3H), 4.70 (s, 1H), 3.80 (s, 3H), 3.35 (m, 2H), 2.95 (m, 1H), 2.15 (m,2H). ¹³C-NMR(CDCl₃+DMSO d₆): 185.31 and 185.25 s, 162.43 and 161.43 d;147.12 and 146.84 s; 144.61 and 144.37 s; 142.33 and 141.97 d, 129.27and 129.13 s, 126.62 and 126.40 s, 123.40 and 123.25 s, 116.67 and116.46 d, 114.27 and 112.74 s, 87.00 and 86.86 d, 56.01 q, 52.38 and51.55 s, 46.18 and 45.80 t, 40.58 t, 37.68 and 36.86 t, 34.26 t.

EXAMPLE 12

(4α,6β)-4 a, 5,9,10,11,12-hexahydro-3methoxy-11-methyl-6H-benzofuro [3a, 3,2,-ef] [2]benzazepin-6-ol (galanthamine)

(general formula (I) where: r₂=R₄=Me, X₁=X₂=Y₂=H,Y₁=OH)

Method 1:

4.6 g (121.21 mmol) of LiAlH₄ in 80 ml of absolute THF are initiallyintroduced into a 1 1 three-necked flask and are cooled to 0° C. 7.36 g(19.47 mmol) of the compound (V) (R₁=H, R₄=CHO, X₁=Br, X₂=H, Y₁,Y₂=)) in460 ml of absolute THF are added dropwise to this suspension in thecourse of 5 minutes, with vigorous stirring, and the mixture is stirredat 0° C. for 1 hour and boiled under reflux for 21 hours. The reactionmixture is then transferred to a 1 1 one-necked flask and cooled to 0°C., excess LiAlH₄ is destroyed with a few drops of H₂O and the solventis removed in vacuo. H₂) is added to the residue and the pH is broughtto 1 with 2N HCl solution. The reaction solution is shaken and warmed upuntil the precipitate has dissolved. The pH is then brought to pH 9 with2N NaOH, ethyl acetate is added to the cloudy solution, the mixture isshaken thoroughly and the precipitate which has separated out isfiltered off. The organic phase is separated off and the aqueous phaseis extracted with ethyl acetate. The combined organic phases are driedover Na₂SO₄ and filtered and the solvent is removed in vacuo.Purification of the residue by chromatography (300 g of SiO₂, withCHCl₃:MeOH=97:3→95:5) gives colorless crystals.

Yield: 2.23 g (40.03%)

Method 2:

A solution of 365 mg (1.0 mmol) of the compound (I) (R₂=R₄=Me, X₁=Br,X₂=Y₂=H, Y₁=OH) in 4 ml of anhydrous THF is added dropwise to asuspension of 240 mg (6.3 mmol) of LiAlH₄ in 4 ml of absolute THF at 0°C., and the mixture is stirred at room temperature for 1 hour and thenat the reflux temperature for 23 hours. The reaction mixture is nowcooled to 0° C., excess reducing agent is destroyed with H₂O and themixture is diluted with 50 ml of ethyl acetate and 50 ml of concentratedNH₄OH. After shaking, the precipitate which has separated out isfiltered [sic], the organic phase is separated and the aqueous phase iswashed with ethyl acetate. The combined organic phases are dried overNa₂SO₄ and filtered and the solvent is removed in vacuo. Purification ofthe residue by chromatography (25 g of SiO₂, CHCl₃:MeOH=99:1→96:4) gives140 mg (49%) of the compound (I) (R₂=R₄=Me, X₁=X₂=Y₂=H, Y₁=OH).

Method 3:

1.0 ml of HCOOH is added dropwise to a suspension of 100 mg (0.27 mmol)of the compound (I) (R₂=R₄=Me, X₁=Br, X₂=H=Y₂=H, Y₁=OH) and 10 mg of 10%strength Pd/C in 3 ml of Et₃N. After, the mixture has been stirred atthe reflux temperature for 2.5 hours, the Pd/C is filtered off throughCelite, the solvent is removed in vacuo and the residue is taken up inCH₂Cl₂. The organic solution is washed twice with saturated NH₄Clsolution and once with H₂O and dried with Na₂SO₄ and the solvent isevaporated off in vacuo. The residue is separated by means of columnchromatography (9 g of SiO₂, CHCl₃: MeOH=95.5).

Yield: 62 mg (79%) of the compound (I) (R₂=R₄=Me, X₁=X₂=Y₂=H, Y₁=OH)

Melting point: 119 to 121° C.

Molecular weight C₁₇H₂₁NO₃:287.34

EXAMPLE 13

(4α,6β)-4 a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-6H-benzofuro [3 a,3,2-ef] [2]benzazepin-6-ol (bromogalanthamine)

(general formula (I) where: R₂=R₄=Me, X₁=Br, X₂=Y₂=H, Y₁=OH) and

(4α,6α)-4 a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11methyl6H-benzofuro [3 a, 3,2-ef] [2]benzazepin-6-ol (epibromogalanthamine)

(general formula (I) where: R₂=R₄=Me, X₁=Br, X₂=Y₁=H, Y₂=OH)

10 ml (36 mmol) of 1.5M DiBal-H solution in toluene is added dropwise toa suspension of 8.0 g (21 mmol) of the compound (V) (R₂=Me, R₄=CHO,X₁=Br, X₂=H, Y₁,Y₂=O) in 150 ml of toluene at 0° C. The reaction isstirred at room temperature for 1 hour, the residual reducing agent isdestroyed with H₂O, and 12 ml of concentrated NH₄OH are then added.After the mixture has been stirred at room temperature for 20 minutes,the material which has precipitated out if filtered off, the organicphase is separated off and the aqueous phase is washed with 50 ml oftoluene. The combined organic phases are dried over Na₂SO₄ and filteredand the solvent is removed in vacuo. The residue (7.7 g) is separated bymeans of column chromatography.

Yield: 3.2 g (45.1%) of the compound (I) where (R₂=R₄=Me, X₁=Br,X₂=Y₂=H, Y₁=OH) and 0.8 g (20.7%) of the compound (I) (R₂=R₄=Me, X₁=Br,X₂=Y₁=H, Y₂=OH),

Data for bromogalanthamine (compound (I) where R₂=R₄=Me, X₁=Br, X₂=Y₂=H,Y₁=OH):

Molecular weight: C₁₇H₁₉BrNO₃:365.23

IR(KBr): 689.03 m; 778.57 m; 839.37 m; 989.86 m; 1050.66 s; 1212.43 s;1279.87 s; 1434.08 s; 14.72 s; 1613.99 s; 2667.39 m; 3370 to 3778br

¹H-NMR (CDCl₃): 6.9 (s, 1 H); 6.06 (m, 2 H); 4.60 (d, 1 H); 4.15 (t, 1H); 3.92 (d, 1 H); 3.82 (s, 3 H); 3.24 (m, 1 H); 2.98 (dt, 1 H); 2.68(dd, 1 H); 2.42 (s, 3 H); 2.05 (m, 2 H); 1.60 (dt, 1 H).

¹³C-NMR (CDCl₃): 145.32 s; 144.00 s, 133.96 s; 127.95 d; 127.68 s;126.51 d; 115.61 d; 114.22 s; 88.56 d; 61.58 d; 58.56 t; 55.95 q; 53.26t; 48.56 s; 42.06 q; 33.47 t; 2969 t.

Data for epibromogalanthamine (compound (I) where R₂=R₄=Me, X₁=Br,X₂=Y₁=H, Y₂=OH):

Molecular weight: C₁₇H₁₉BrNO₃:365.23

IR(KBr): 667:95 w; 752 m; 836.68 m; 1040.31 s; 1208.39 s; 12.82 m;1435.25 m; 1485.72 m; 1512.94 w; 1558.27 w; 1615.19 m; 1667.14 w;2943.24 w; 3360 to 3575br.

¹H-NMR (CDCl₃): 6.85 (s, 1 H); 5.96 (AB, 2H); 4.69 (m, 2 H); 4.28 (d, 1H); 3.90 (d, 1 H); 3.83 (s, 1H); 3.25 (m, 1 H), 2.95 (m, 1 H); 2.85 (dt,1 H); 2.36 (s, 3 H); 2.15 (td, 1 H); 1.69 (m, 2 H).

¹³C-NMR (CDCl₃+DMSO-d₆): 145.84 s; 143.49 s; 133.89 s; 133.14 d; 126.12s; 124.35 d; 115.04 s; 113.01 s; 88.26 d; 61.10 d; 57.44 t; 55.58 q;52.84 t; 47.86 s; 41.20 q; 33.35 t; 31.43 t.

EXAMPLE 14

(4α, 6α) -4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef] [2]benzazepin-6-ol(epigalanthamine)

(general formula (I) where: R₂═R₄═Me, X₁═X₂═Y₁═H, Y₂═OH)

A solution of 365 mg (1.0 mmol) of the compound (I) (R₂═R₄═Me, X₁═Br,X₂═Y₁═H, Y₂═OH) in 4 ml of absolute THF is added dropwise to asuspension of 240 mg (6.3 mmol) of LiAlH₄ in 4 ml of anhydrous THF at 0°C. and the mixture is stirred at room temperature for 1 hour and then atthe reflux temperature for 23 hours. The reaction mixture is now cooledto 0° C., excess reducing agent is destroyed with H₂O and the mixture isdiluted with 50 ml of ethyl acetate and 50 ml of ethyl acetate [sic] and50 ml of concentrated NH₄OH. After shaking, the precipitate which hasseparated out is filtered [sic], the organic phase is separated off andthe aqueous phase is washed with ethyl acetate. The combined organicphases are dried over Na₂SO₄ and filtered and the solvent is removed invacuo. The residue is separated by means of column chromatography (25 gof SiO₂), CHCl₃:MeOH=99.1→96:4).

Yield: 140 mg (49%) of 1 (R₂═R₄═Me, X₁═X₂═Y₁═H, Y₂═OH)

Melting point: 199 to 201° C.

Molecular weight: C₁₇H₂₁NO₃:287.34

EXAMPLE 15

(4α, 6β)-4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol (N-demethyl-bromogalanthamine)

(general formula (I) where: R₂═Me, X₁═Br, R₄═X₂═Y₂═H, Y₁═OH)

100 ml (100 mmol) of a 1 M solution of L-Selektride are added dropwiseto a suspension of 10 g (26.4 mmol) of (1) (R₂═Me, R₄═CHO, X₁═Br, X₂═H,Y₁═Y₂═O) in 200 ml of THF at 0° C. in the course of 30 minutes. Afterthe mixture has been stirred at 0° C. for 60 minutes, the complex formedwith the reagent is destroyed with H₂O, and 100 ml of 25% strength NH₄OHsolution are added to the reaction mixture. After the mixture has beenstirred at room temperature for 30 minutes, the solvent is concentratedto half in vacuo, the mixture is transferred into a shaking funnel, 100ml of 25% strength NH₄OH solution are added and the mixture is extractedwith 3×200 ml of CH₂Cl₂. The combined organic phases are dried withNa₂SO₄ and filtered and the solvent is evaporated off in vacuo.Purification of the residue by chromatography (650 g of SiO₂ silica gelCICl₃:MeOH=95:5→9:1) gives a colorless foam.

Yield: 7.3 g (75.8%)

C₁₆H₁₈BrNO₃:352:21

IR(KBr): 748.19 m; 793.11 m; 828.59m; 927.62w; 991.65w; 1058.8s;1214.79s; 1281.61s; 14.29s; 1488.49s; 1571.11w; 1616.51s; 2912.36s; 3280to 3420br.

UV(MeOH): λ_(max):225.0 and 297.5 nm.

¹H—NMR (CDCl₃): 6.85 (s, 1H); 6.02 (AB, 2 H); 4.53 (s, 1H); 4.81 and4.48 (AB, 2H); 4.10 (m, 1H); 3.78 (s, 3H); 3.22 (m, 2H); 2.63 (dd, 1H);2.29 (s, br, 2H); 2.00 (m, 1H); 1.78 (m, 2H).

¹³C—NMR (CDCl₃): 145.79s; 143.96s; 134.06s; 131.64s; 127.87d; 126.83d;115.46d; 113.02s; 88.44d; 61.67d; 56.04q; 52.65t; 49.23s; 46.59t;39.81tt; 29.71t.

EXAMPLE 16

(4α,6β)-4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol (N-demethyl-bromogalanthamine).

(general formula (I) where: R₂═Me, X₁═Br, R₄═X₂═Y₂═H, Y₁═OH) and(4α,6β)-4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol (N-dimethyl-epibromogalanthamine)

(general formula) (I) where: R₂═Me, X₁═Br, R₄═X₂═Y1 [sic]═H, Y2[sic]═OH)

3.0 g (11.8 mmol) of LiAlH(t-B₄O)₃ in 15 ml of THF are added dropwise toa suspension of 1.0 g (2.6 mmol) of (I) (R₂═Me, R₄═CHO, X₁═Br, X₂═H,Y₁═Y₂═O) in 5 ml of THF at 0° C. in the course of 30 minutes. After thereaction mixture has been stirred at 0° C. for 30 minutes, it is boiledunder reflux. After the mixture has been boiled for 22 hours, thecomplex formed with the reagent is destroyed with H₂O, and 10 ml of 25%strength NH₄OH solution are added to the reaction mixture. After themixture has been stirred at room temperature for 30 minutes, the solventis concentrated to half in vacuo, the mixture is transferred into ashaking funnel, 10 ml of 25% strength NH₄OH solution are added and themixture is extracted with 3×20 ml of CH₂Cl₂. The combined organic phasesare dried with Na₂SO₄ and filtered and the solvent is evaporated off invacuo. Purification of the residue by chromatography (60 g of SiO₂silica gel CHCl₃:MeOH=95:5→9:1→8:2) gives two products.

300.0 mg (32.2% of N-demethyl-bromogalanthamine

(general formula (I) where R₂═Me, X₁═Br, R₄═X₂═Y₂═H, Y₁═OH) as acolorless foam and 270 mg (29.0% of N-dimethyl-bromogalanthamine(general formula (I) where R₂═Me, X₁═Br, R₄═X₂═Y₁═H, Y₂═OH) as acolorless foam.

Data for N-demethyl-epibromo-galanthamine:

Molecular weight: C₁₆H₁₈BrNO₃:352.21

IR(KBr): 781.60w; 834.28w; 976.63w; 1050.28m; 1179.73m; 1211.87m;1280.07m; 1435.24m; 1486.10m; 1616.37m; 2923.54w: 3700-2900 mbr.

¹H—NMR (CDCl₃): 6.86 (s, 1H); 5.92 (AB, 2H); 4.56 (m, 2H); 4.50 and 3.82(AB, 2H); 3.80 (s, 3H); 3.28 (m, 2H); 2.52 (m, 1H); 2.20-1.70 (m, 3H).

¹³C—NMR (CDCl₃): 146.73s; 143.91s; 134.10s; 132.17s; 132.17d; 131.48d;126.34d; 115.34d; 112.44s; 88.51d; 62.81d; 56.10q; 52.34t; 49.25s;46.82t; 40.52t; 32.07t.

EXAMPLE 17

(4α6β)-4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-6H-benzofuro[3a,3,2,-ef][2]benzazepin-6-ol (N-demethyl-bromogalanthamine)

(general formula (I) where: R₂═R₄═Me, X₁═Br, X₂═Y₂═H, Y₁═OH)

Method 1:

5 ml of 89% strength HCOOH and 5 ml of 37% strength CH₂O are added to asolution of 2.0 g (5.6 mmol) of (I) (R₂═Me, X₁═Br, R₄═X₂═Y₂═H, Y₁═OH) in20 ml of H₂O) and the mixture is boiled under reflux. After the reactionmixture has been boiled for 15 minutes, it is diluted with H₂O, the pHis brought to 9 with 25% strength NH₄OH and the mixture is extractedwith 3×20 ml of CH₂Cl₂. The combined organic phases are dried withNa₂SO₄ and filtered and the solvent is evaporated off in vacuo.Purification of the residue by chromatography 150 g of SiO₂ silica gelCHCl₃:MeOH=97:→95:5) gives a colorless foam.

Yield: 2.0 g (96.4%)

Method 2:

100 ml (100 mmol) of a 1 M solution of L-Selektride are added dropwiseto a suspension of 10 g (26.4 mmol) of (I) (R₂═Me, R₄═CHO, X₁═Br, X₂═H,Y₁═Y₂═O) in 200 ml of THF at 0° C. in the course of 30 minutes. Afterthe mixture has been stirred at 0° C. for 60 minutes the reagent isdestroyed with H₂O, and 100 ml of 25% strength NH₄OH solution are addedto the reaction mixture. After the mixture has been stirred at roomtemperature for 30 minutes, the solvent is concentrated to half invacuo, the mixture is transferred into a shaking funnel, 100 ml of 25%strength NH₄OH are added and the mixture is extracted with 3×200 ml ofCH₂Cl₂. The combined organic phases are dried with Na₂SO₄ and filteredand the solvent is evaporated off in vacuo. 50 ml of H₂O, 30 ml of 98%strength HCOOH and 30 ml of 37% strength CH₂O solution are added to theresidue and the reaction mixture is boiled under reflux. After themixture has been boiled for 15 minutes, the reaction is neutralized withNH₄OH and the extracted with 3×200 ml of CH₂Cl₂. The combined organicphases are dried over Na₂SO₄ and filtered and the solvent is evaporatedoff in vacuo. Purification of the residue by chromatography (600 g ofSiO₂ silica gel CHCl₃:MeOH=9:1→8:2) gives a colorless foam.

Yield: 6.4 g (66.2%).

EXAMPLE 18

Optical separation of (±)galanthamine

A solution of 672.2 mg (1.74 mmol) of (+)di-p-toluyl-D-tartaric acid in4 ml of MeOH is added to a solution of 500 mg of (±)galanthamine (1.74mmol), compound (I) (R₂═R₄═Me, X₁═X₂═Y₂═H, Y₁═OH), in 1.0 ml of MeOH atroom temperature. After the mixture has been left to stand in arefrigerator for 24 hours, the crystalline substance which hasprecipitated out is filtered and washed with MeOH. The mother liquor issaved for the other isomer. Recrystallization from EtOH gives 450 mg of(−)galanthamine (+)di-p-toluoyl-tartrate (compound (II), R₂═R₄═Me,R₅═X₁═X₂═Y₂═H, Y₁═OH, Z═(+)di-p-toluoyl-tartrate), melting point: 182 to184° C. The free base is liberated from the salt with CHCl₃/NH₄OH.[α]_(D)=−101.8° C.

The methanolic mother liquor is evaporated, the base is liberated withCHCl₃/NH₄OH and dissolved in 0.5 ml of MeOH, and a solution of 215 mg(0.55 mmol) of (−)di-p-toluyl-L-tartaric acid is added. After themixture has been left to stand in a refrigerator for 24 hours, thematerial which has precipitated out is filtered and washed with MeOH.Recrystallization from EtOH gives 242 mg of(+)galanthamine(−)di-p-toluoyl-tartrate (compound (II) R₂═R₄Me,R₅═X₁═X₂═Y₂═H, Y₁═OH, Z═(−)di-p-toluoyl-tartrate), melting point: 144 to148° C. The salt is converted into the free base with CHCl₃ [sic]/NH₄OH.[α]_(D)=+98.9° C.

EXAMPLE 19

4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-formyl-6H-benzofuro[3a,3,2-ef][2]benzazepine 6-ethylene ketal (general formula (I) where R₂═Me,R₄═CHO, X₁═Br, X₂═H, Y₁, Y₂═—O—(CH₂)₂—O—)

5.0 g of the compound (I) where R₂═Me, R₄═CHO, X₁═Br, X₂═H, Y₁, Y₂═O,10.0 g ethylene glycol and 0.05 g of p—TsOH were heated to the refluxtemperature in 100 ml of toluene (2-phase mixture at room temperature)with vigorous mechanical stirring (homogeneous from about 90° C.) andthe mixture was boiled for 2 hours, water being separated off. Aftercooling, the phases were separated (the toluene phase being the upperphase), the ethylene glycol phase was extracted twice with 20 ml oftoluene and the combined toluene phases were shaken with 2×50 ml ofsaturated NaHCO₃ solution, dried over Na₂SO₄ and evaporated.

Yield: 5.40 g of a yellowish foam (96.7% of theory crude), whichcrystallized overnight.

Column chromatography of 1.0 g (60 g of silica gel 60, CHCl₃/1 to 2% ofMeOH) gave: 0.62 g of a colorless foam which crystallized from EtOAc.

Melting point: 212 to 214° C.

Molecular weight: C₁₉H₂₀BrNO₅:422.28

¹H—NMR (CDCl₃): 812 (d, H), 6.87 (s, H), 6-06 (t, H), 5.72 (d,H), 5.64(d, H/2), 5.11 (d/H2), 4.54 (b, H), 4.48 (d, H/2), 4.31 (d, H/2),3.50-4.10 (m, 6H), 3.82 (s, 3H), 2.65 (d, H), 2.27 (d, H), 1.74-2.10 (m,2H).

¹³C—NMR (CDCl₃): 162.40, 161.65, 147.08, 144.81, 144.55, 132.14, 131.96,127.68, 127.48, 115.68, 115.43, 126.71, 126.44, 113.12, 111.59, 102,04,87.07, 86.90, 65.14, 64.23, 55.88, 51.43, 46.11, 48.41, 40.67, 39.27,35.96, 32.94.

EXAMPLE 20

4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-formyl-6H-benzofuro[3a,3,2-ef][2]benzazepine 6-propylene ketal (general formula) (I) where R₂═Me,R₄═CHO, X₁═Br, X₂═H, Y₁,Y₂═—O—CH₂—CH(CH₃)—O—)

100 g of the compound (I) where R₂═Me, R₄═CHO, X₁═Br, X₂═H, Y₁,Y₂═O, 100g of propylene glycol and 0.5 g of H₂SO₄ were heated to the refluxtemperature in 800 ml of toluene (2-phase mixture at room temperature)with vigorous mechanical stirring (homogeneous from about 90° C.) andthe mixture was boiled for 14 hours, water being separated off. Aftercooling, the phases were separated (the toluene phase being the upperphase), the propylene glycol phase was extracted twice with 100 ml oftoluene and the combined toluene phases were shaken with 2×200 ml ofsaturated NaHCO₃ solution, dried over Na₂SO₄ and evaporated.

Yield: 115.3 g of a yellowish foam (100% of theory crude), whichcrystallized overnight.

Column chromatography of 1.0 g (60 g of silica gel 60, CHCl₃/1 to 2% ofMeOH) gave: 0.80 g of a colorless foam which crystallized from EtOAc.

Melting point: 170 to 171° C.

Molecular weight: C₂₀H₂₂BrNO₅:436.28

¹H—NMR (CDCl₃): 8.12 (d, H), 6.88 (s, H), 5.96-6.17 (m, H), 5.75 (dd,H), 5.68 (d, H/2), 5.10 (d, H/2), 4.53 (b, H), 4,48 (d, H/2), 4.31 (d,H/2),3.12-4.38 (m, 5H), 3.82 (s, 3H), 2.56-2.80 (m, H), 2.05-2.35 (dd,H), 1.83-2.05 (m, 2H), 1.22-1.47 (m, 3H).

¹³C—NMR(CDCl₃): 162.48, 161.72, 147.17, 144.89, 144.64, 132.16, 129.04,128.51, 128.57, 127.82, 127.70, 127.61, 115.70, 115.48, 127.09, 126.77,126.5, 113.20, 111.66, 102.38, 102.22, 87.25, 87.07, 73.38, 72.46,71.67, 71.41, 71.23, 70.55, 70.28, 55.92, 51.52, 46.18, 48.43, 40.77,39.29, 36.07, 35.97, 34.58, 33.68, 33.44, 33.13, 18.68, 17.59, 17.45.

Note NMR¹ diastereomers: Because of the chiral center additionallyintroduced by means of the (+/−)propylene group, diastereomers areformed which result in an additional splitting of the signal in additionto that caused by the formyl group.

EXAMPLE 21

4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a3,2-ef][2]benzazepine 6-ethylene ketal (general formula (I) where R₂═Me,R₄═CH₃, X₁═X₂═H, Y₁, Y₂═—O—CH₂-CH₂—O—).

2.0 g of the compound (I) where R₂═Me, R₄═CHO, X₁═Br, X₂═H,Y₁,Y₂═O—(CH₂)₂—O— were suspended in 50 ml of anhydrous THF, thesuspension was cooled to 0° C., 20 ml of LiAlH₄(diethyl ether (1M) wereadded dropwise in the course of 5 minutes and the mixture was warmed toroom temperature. It was then stirred at the reflux temperature (45 to52° C.) for 12 hours and cooled, 3 ml of THF/water (2:1) were addeddropwise, and the mixture was rendered alkaline with 50 ml of NH₄OH(25%) and extracted 4 times with 50 ml of EtOAc. The organic phases weredried over Na₂SO₄ and evaporated.

Yield: 1.52 g of a yellowish oil (92.9% of theory).

Column chromatography (80 g of silica gel 60, EtOAc/MeOH 8:2) gave: 0.82g of colorless crystals

Melting point: 109-110° C.

Molecular weight: (C₁₉H₂₃NO₄): 329.40

¹H—NMR (CDCl₃): 1.65 (ddd, 1H), 2.10 (ddd, 1H), 2.15 (dd, 1H), 2.40 (s,3H), 2.65 (dd, 1H), 3.05 (ddd, 1H), 3.20 (ddd, 1H), 3.60 (d, 1H), 3.80(s, 3H), 3.90-4.05 (m, 4H), 4.10 (d, 1H), 4.55 (dd, 1H), 5.65 (d, 1H),6.15 (d, 1H), 6.55, 6.60 (2x d, 2H)

¹³C—NMR (CDCl₃): 33.2 (t), 33.8 (t), 41.7 (q), 47.8 (t), 53.8 (s), 55.5(q), 60.2 (t), 64.0, 65.0 (2x t), 87.1 (d), 102.5 (s), 110.9 (d), 121.1(d), 125.9 (d), 128.7 (s), 128.9 (s), 131.8 (d), 143.8 (s), 146.5 (s).

EXAMPLE 22

4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine 6-(2-hydroxyethyl) ether (general formula) (I) whereR₂═Me, R₄═CH₃, X₁═X₂═H, Y₁═ —O—CH₂—CH₂—OH, Y₂═H)

1.0 g of the compound (I) where R₂═Me, R₄═CHO, X₁═Br, X₂═H,Y₁,Y₂═O—(CH₂)₂—O— were dissolved in 25 ml of THF, the solution wascooled to 0° C., 9 ml of LiAlH₄/THF (1M) were added dropwise in thecourse of 5 minutes and the mixture was stirred at 0° C. for 30 minutes.It was now heated at the reflux temperature for 48 hours and cooled, 25ml of NH₄OH (25% strength) were added dropwise and the mixture wasextracted 4 times with 20 ml of EtOAc. The organic phases were driedover Na₂SO₄and evaporated:

Yield: 0.76 g of a yellowish oil (92.9% of theory).

Column chromatography (40 g of silica gel 60, CHCl₃/2-7% of MeOH) gave:0.62 g of a colorless foam.

Molecular weight: (C₁₉H₂₄NO₄): 330.40

¹H—NMR (CDCl₃): 1.52 (dd, H), 1.85 (td, H), 2.10 (dt, H), 2.35 (s, 3H),2.82 (d, H), 3.02 (d, H), 3.20 (b, H, D₂O-exchangeable), 3.24 (d,H),3.53-3.72 (m, 5H), 3.78 (s, 3H), 3.94 (t, H), 4.10 (d, H), 4.54 (b, H),5.94 (d, H), 6.22 (d, H), 6.33 (d, H), 6.61 (d, H).

¹³C—NMR (CDCl₃): 26.50, 34.35, 41.57, 48.01, 53.57, 55.72, 60.17, 61.78,68.42, 69.48, 86.85, 111.06, 121.22, 124.60, 128.95, 129.21, 131.86,143.88, 146.15.

EXAMPLE 23

4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-demethyl-6H-benzofuro[3a,3,2-ef][2]benzazepine 6-ethylene ketal (general formula (I) where R₂═Me, R₄═H,X₁═Br, X₂═H, Y₁,Y₂═—O—CH₂—CH₂—O—)

0.11 g of the compound (I) where R₂═Me, R₄═CHO, X₁═Br, X₂═H,Y₁,Y₂═O—(CH₂)₂—O— was dissolved in 10 ml of THF, the solution was cooledto 0° C., 0.3 ml of LiAlH₄/THF (1M) was added dropwise in the course of5 minutes and the mixture was stirred at 0° C. for 30 minutes. ExcessTHF was evaporated off, the residue was taken up in 10 ml of NH₄OH (25%strength) and the mixture was extracted 3 times with 10 ml of EtOAc. Theorganic phases were dried over Na₂SO₄and evaporated.

Yield: 0.13 g of an oily crude product.

Column chromatography (5 g of silica gel 60, CHCl₃/2-7% of MeOH) gave:80 mg of a colorless foam (77.9% of theory)

Molecular weight: (C₁₈H₂₀BrNO₄): 394.27

¹H—NMR (CDCl₃): 6.82 (s, H), 6.16 (d, H), 5.67 (d, H), 4.55 (b, H), 4.48(d, H), 3.84-4.08 (m, 5H), 3.78 (s, 3H), 3.04-3.37 (m, 2H), 2.62 (bd,H), 2.15 (dd, H), 1.70-1.95 (m, 3H),

¹³C—NMR (CDCl₃): 146.69, 144.00, 133.07, 131.29, 129.00, 112.16, 126.30,115.25, 102.37, 87.28, 65.11, 64.17, 55.78, 52.46, 49.02, 40.13, 33.06.

EXAMPLE 24

4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-benzyl-6H-benzofuro[3a,3,2-ef][2]benzazepine 6-ethylene ketal (general formula) (I) where R₂═Me,R₄═—CH₂—Ph, X₁═Br, X₂H, Y₁,Y₂═—O—CH₂—CH₂—O—)

250 mg (0.63 mmol) of the compound (I) where R₂═Me, R₄═H, X₁═Br, X₂═H,Y₁,Y₂═O—(CH₂)₂—O— (N-demethyl bromonarwedine ethylene ketal) and 63 mg(0.63 mmol) of triethylamine were initially introduced into 15 ml ofabsolute tetrahydrofuran, 108 ml (0.63 mmol) of benzyl bromide wereadded at room temperature and the mixture was then stirred for 24 hours.50 ml of water were added to the reaction mixture and the aqueous phasewas extracted 3 times with 20 ml of ethyl acetate each time. Thecombined organic phases were washed once with saturated aqueous sodiumchloride solution, dried (over Na₂HO₄ [sic]) and evaporated.

Yield: 260 mg (84.7% of theory) of colorless crystals.

Melting point: 118-119° C.

TLC: EtOAc: MeOH=9:1

Molecular weight: (C₂₅H₂₆BrNO₄): 484.39

¹H-NMR (CDCl₃; d (ppm)): 1.65 (ddd, 1H), 2.05-2.30 (m, 2H), 2.65 (dd,1H), 3.00-3.30 (m, 2H), 3.70 (s, 2H), 3.80 (s, 3H), 3.90-4.20 (m, 5H),4.35 (dd, 1H), 4.60 (ddd, 1H), 5.70 (d, 1H), 6.25 (d, 1H), 6.85 (s, 1H),7.25-7.30 (m, 5H).

¹³C-NMR (CDCl₃, d (ppm)): 33.1 (d), 33.4 (t), 48.5 (s), 50.7 (t), 55.8(q), 56.4 (t), 56.9 (t), 64.2, 65.1 (2^(*)t), 87.4 (d), 102.3 (s), 113.6(s), 115.6 (d), 126.6, 128.2, 128.9 (3^(*)d), 127.1 (d), 3.1 (s), 137.9(s), 144.2 (s), 146.3 (s).

EXAMPLE 25

4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-demethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one (general formual (I) where R₂=Me, R₄=H, X₁=Br, X₂=H,Y₁,Y₂=O)=N-demethylbromonarwedine

250 mg (0.63 mmol) of the compound (I) where R₂=Me, R₄=H, X₁=Br, X₂=H,Y₁,Y₂=O-(CH₂)₂-O(=N-demethylbromonarwedine ethylene ketal) weredissolved in 20 ml of 2N hydrochloric acid and the solution was heatedat 100° C. for 15 minutes. 20 ml of concentrated aqueous ammonia werethen added, the reaction mixture was heated briefly and cooled, and aprecipitate was obtained, which was filtered off with suction and driedat 50° C.(20 mm.

Yield: 130 mg (58.6% of theory) of colorless crystals

Melting point: 173-174° C.

TLC: EtOAc: MeOH=8:2

Molecular weight: (C₁₆H₁₆Br, NO₃), 350.21

¹H-NMR (DMSO-d6, d (ppm)): 1m90-2.15 (m, 2H), 2.75 (dd, 1H), 2.95 (dd,1H), 3.10-3.35 (m, 2H), 3.75 (s, 3H), 3.90 (d, 1H), 4.40 (d, 1H), 4.55(dd, 1H), 5.90 (d, 1H), 6.90 (s, 1H), 7.05 (d, 1H)

¹³C-NMR (DMSO-d6, d (ppm)): 36.3 (d), 37.0 (t), 45.6 (s), 49.5 (t), 51.3(t), 55.9 (g), 87.6 (d), 112.5 (s), 116.0 (d), 126.6 (d), 129.6 (s),132.0 (s), 143.7 (s), 144.8 (d), 146.6 (s), 194.0 (s)

EXAMPLE 26

4a,5,9,10,11,12-hexahydro-3-methoxy-11-demethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one (general formula (I) where R₂=Me, R₄=H, X₁=X₂=H,Y₁,Y₂=O)

EXAMPLE 27

4a,5,9,10,11,12-hexahydro-3-methoxy-11-benzyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one (general formula (I) where R₂=Me, R₄=CH₂-Ph,X₁,X₂=H, Y₁,Y₂=O)

EXAMPLE 28

4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine 6-propylene ketal (general formula (I) where R₂=Me,R₄=CH₃, X₁=X₂=H, Y₁,Y₂=O—CH₂-CH(CH₃)-O-)

37.5 g of LiAlH₄ were introduced into a predried 4 l multi-necked flaskunder argon, and 800 ml of THF were allowed to run in from a droppingfunnel, the temperature rising to about 45° C. with vigorous foaming(depends on the water content of the THF and of the reaction flask). Asuspension of 114 g of the compound (I) where R₂=Me, R₄=CHO, X₁=bromine,X₂=H, Y₁,Y₂=O—CH₂-CH(CH₃)-O— (crude) in 400 ml of THF was now addeddropwise in the course of 15 minutes, the temperature rising to thereflux temperature (about 65-68° C.). The mixture was now heated at thereflux temperature for 10 hours, with mechanical stirring, and cooledand 100 ml of water in 100 ml of THF were added dropwise, while cooling.

Removal of 10 ml, rendering alkaline with NH₄OH and extraction withEtOAc (3×20 ml) gave, after evaporation, an oily product.

Column chromatography (5 g of silica gel 60, CHCl₃/3-5% of MeOH) of 0.17g gave: 0.1 g of a colorless foam

Molecular weight: (C₂₀H₂₅NO₄): 343.42

¹H-NMR (CDCl₃): 6.60 (dd, 2H), 6.16 (dt, H), 5.68 (dd, H), 4.55 (m, H),4.38-4.00 (m, 3H), 3.80 (s, 3H), 3.68-2.95 (m, 4H), 2.78-2.80 (m, H),2.35 (s, 3H), 2.24-2.02 (m, 2H), 1.62 (bd, H), 1.28 (t, 3H)

¹³C-NMR (CDCl₃): 146.59, 143.92, 132.04, 131.90, 129.57, 129.16, 128.86,128.76, 128.39, 127.44, 126.92, 126.12, 126.02, 121.16, 111.05, 110.90,110.77, 102.87, 102.73, 87.23, 73.15, 72.24, 71.43, 71.12, 70.44, 70.17,60.28, 55.59, 55.53, 55.45, 53.83, 47.87, 47.80, 47.75, 41.80, 41.70,34.84, 33.95, 33.66, 33.37, 18.66, 17.62, 17.43

Note NMR, diastereomers: Because of the chiral center additionallyintroduced by means of the (+/−) propylene group, diastereomers areformed which have the effect of a splitting of the signal in addition tothat caused by the formyl group.

EXAMPLE 29

4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one, narwedine. (General formula (I) where R₂=Me,R₄=CH₃, X₁=X₂=H, Y₁,Y₂=O)

37.5 g of LiAlH₄ were introduced into a predried 4 l multi-necked flaskunder argon, and 800 ml of THF were allowed to run in from a droppingfunnel, the temperature rising to about 45° C. with vigorous foaming(depends on the water content of the THF and of the reaction flask). Asuspension of 114 g of the compound (I) where R₂=Me, R₄=CHO, X₁=bromine,X₂=H, Y₁,Y₂=O—CH₂-CH(CH₃)-O— (crude) in 400 ml of THF was now addeddropwise in the course of 15 minutes, the temperature rising to thereflux temperature (about 65-68° C.). The mixture was then heated at thereflux temperature for 10 hours, with mechanical stirring, and cooled,and 100 ml of water in 100 ml of THF were added dropwise, while cooling.

The pH was then brought to 0 to 1 with 1.25 liters of 2N HCl and 60 mlof concentrated HCl and the mixture was stirred at 60° C. for 30minutes, subsequently transferred into a 5 liter separating funnel,covered with a layer of 1 liter of EtOAc, brought to pH 10 with NH₄OH(about 250 ml) and extracted. The aqueous phase was extracted once morewith 1 l of EtOAc+300 ml of THF, the precipitate was then filtered offover Celite and extraction was carried out a further two times with 500ml of EtOAc. The combined organic phases were dried over Na₂SO₄ andevaporated.

Yield: 64.8 g (86.9% of theory crude) of yellow crystals

Molecular weight: 285.32 (C₁₇H₁₉NO₃)

TLC: CHCl₃/MeOH (5%)

Melting point: 189-192° C.

EXAMPLE 30

(−)narwedine:

122.4 g of (+/−)narwedine were heated at the reflux temperature in 1.9 lof EtOH (96% strength)/triethylamine (9:1) until a homogeneous solutionformed. The mixture was then cooled slowly, 4.0 g of (−)narwedine wereadded at 68° C. and the mixture was stirred at 40° C. for 7 days.Cooling to room temperature, filtration with suction and drying of thecrystalline precipitate gave (−)narwedine (fraction I). The motherliquor was evaporated to dryness, the residue was heated to the refluxtemperature with 200 ml of ethanol (95% strength)/triethylamine (9:1),and 0.4 g of (−)narwedine was added and the mixture stirred at 40° C.for 7 days in the manner described above. Cooling, filtration withsuction and drying gave (−)narwedine (fraction II).

Yield:

Fraction I: 98.6 g of colorless crystals (80.5% of theory)

Fraction II: 7.4 g (6.0% of theory)

Optical rotation: Fraction I: [α]¹⁸=−407° (c=1.5/CHCl₃)

Fraction II: [α]¹⁸=−401° (c=1.5/CHCl₃)

Molecular weight: C₁₇H₁₉NO₃ (285.32)

Melting point: 189-192° C.

EXAMPLE 31

(−)galanthamine

98.6 g of (−)narwedine were added in portions to 1 l of L-Selektride inTHF (1 molar) at room temperature and the mixture was stirred for 1hour. 100 ml of MeOH were then slowly added dropwise, the cloudysolution was evaporated to dryness and the residue was taken up in 3 lof ethanol (96%). The mixture was acidified to pH 1 dropwise with asolution of aqueous 60% strength HBR in EtOH (1:1) and was left to standovernight at 0° C. The crystals which had precipitated out were filteredoff with suction and dried.

Yield: 120.1 g (94.5% of theory)

Optical rotation: [α]¹⁸=−88° (c=1.5/H₂O)

Molecular weight: C₁₇H₂₁NO₃×HBr (368.25)

Melting point: 244-247° C. (decomposition)

EXAMPLE 32

3-Benzoyloxy-N-4-(benzyloxyphenethyl)-6-bromo-4-methoxy-N-methylbenzamide(general formula (Va) with R₁, R₃=benzyl, R₂=R₄=CH₃, X₁=Br, X₂=H, Z₁=O,Z₂=H₂).

20.0 g of 3-benyloxy-6-bromo-4-methoxybenzoic [sic] acid were dissolvedin 250 ml of chloroform p.a. and then 21.6 ml of thionyl chloride (35.29mg=0.297 mol=5 eq.) were added and the mixture was refluxed for 3 hours,and then excess CHCl₃+SOCl₂ were distilled off. The resulting acidchloride was taken up in 150 ml of CHCl₃.

14.24 g of O-benzyl-N-methyltyramine were dissolved in 60 ml of CHCl₃p.a. and then 100 ml of 2N NaOH were added. The dissolved acid chloridewas added to the 2-phase mixture at room temperature with vigorousstirring and the mixture was stirred overnight. The phases were thenseparated. The organic phase was washed with H₂O, dried over Na₂SO₄ andconcentrated by evaporation. The oil obtained was recrystallized from250 ml of ethanol.

Yield: 27.76 g, 83% of theory, of colorless crystals.

TLC: petroleum ether/EtOAc (25:75)

¹H-NMR (CDCl₃): because of the amide there are two conformers(rotamers). 2.69+3.12 (2s, each 1.5H); 2.95+3.21 (2t, each 1H); 3.75 (t,1H); 3.9 (s, 3H) 4.96-5.14 (m, 4H), 7.1-7.48 (m, 16H).

¹³C-NMR (CDCl₃): 32.26, 36.55, 32.48, 33.39, 48.75, 52.34, 56.14, 70.92,71.10, 112.82, 113.05, 114.77, 115.69, 127.23, 128.47, 129.73, 129.78.

EXAMPLE 33

6-Bromo-3-hydroxy-N-(4-hydroxyphenethyl)-4-methoxy-N-methylbenzamide(general formula (Va) with R₁=R₃=H, R₂=R₄=CH₃, X₁=Br, X₂=H, Z₁=O,Z₂=H₂).

5.0 g of3-benzyloxy-N-4-(benzyloxyphenethyl)-6-bromo-4-methoxy-N-methylbenzamide(general formula (Va) with R₁,R₃=benzyl, R₂=R₄=CH₃, X₁=Br, X₂=H₁, Z₁=O,Z₂=H₂) were heated with 50 ml of ethanol and 21.6 ml of HBr to 60° C.and the heated mixture was stirred for 9 hours. The solution was slowlypoured into 1 l of ice-water and was stirred for two hours to allow theproduct to crystallize. The precipitate was filtered off with suction,washed with water and dried.

Yield: 3.23 g (95.22% of theory) of colorless crystals.

TLC: CHCl₃:MeOH=9:1

Melting point: 162-166.5° C.

¹H-NMR (CDCl₃/DMSO): because of the amide there are two isomers.2.49+2.81 (2s, each 1.5H); 3.08+3.42 (2t, each 1H), 3.65 (s, 3H);6.43-6.6 (m, 4H); 6.72 (s, 1H); 6.88 (s, 1H), 8.31-8.59 (b, 2H).

¹³C-NMR (CDCl₃/DMSO): 32.08+33.52, 32.36+36.54, 48.91+54.49, 55.92,113.97, 114.39, 115.43+115.28, 129.44+129.30, 168.61+168.97.

EXAMPLE 34

4a,5,9,10,11,12-Hexahydro-1-bromo-3-methoxy-11-methyl-12-oxo-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one (general formula (Ia) with R₂=R₄=CH₃, X₁=Br, X₂=H,Y₁,Y₂=O, Z₁=O, Z₂=H₂).

40.5 g of potassium hexacyanoferrate(III) (123 mol) and 18 g of K₂CO₃(0.13 mol) were dissolved in 2.7 l of toluene and 180 ml of water andthe solution was heated to 60° C. Then 9.0 g of6-bromo-3-hydroxy-N-(4-hydroxyphenethyl)-4-methoxy-N-methylbenzamide(general formula (Va) with R₁,R₃=H, R₂=R₄=CH₃, X₁=Br, X₂=H, Z₁=O, Z₂=H₂)(0.024 mol) were added. The reaction mixture was subjected to vigorousmechanical stirring for 35 minutes. The resulting polymer [lacuna]filtered over Celite. The aqueous phases were separated off, and thetoluene phase was washed with saturated NaCl, dried over Na₂SO₄ andconcentrated by evaporation.

Crude yield: 5.39 g (60.22% of theory) of a yellowish oil.

1.8 g were chromatographed over 100 g of silica gel (eluent:CHCl₃:MeOH=98:2).

Yield: 1.13 g (37.8% of theory) of colorless crystals.

TLC: CHCl₃:MeOH=95:5

Melting point: 218-222° C.

¹H-NMR (CDCl₃): 1.92+2.48 (dd, 2H); 2.75+3.1 (dd, 2H); 3.34+3.82 (dd,2H); 3.91 (s, 3H); 4.83 (t, 1H); 5.9-6.0+6.3-6.39 (dd, 2H), 7.11 (s,1H).

¹³C-NMR (CDCl₃/DMSO): 34.00, 36.44+36.58, 48.44, 48.55, 56.31, 89.15,113.88, 118.55, 122.84, 125.84, 129.35, 145.60, 146.02, 146.61, 164.57,192.93

EXAMPLE 35

4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-12-oxo-6H-benzofuro[3a,3,2-ef][2]benzazepine-6,6-propylene glycol ketal (general formula (Ia) withR₂=R₄=CH₃, X₁=Br, X₂=H, Y₁,Y₂=O—CH₂CH(CH₃)O—, Z₁=O, Z₂=H₂).

1 g of precursor (12) (0.0026 mol), 50 ml of toluene, 2 ml of propyleneglycol and 0.1 g of p-toluene-sulfonic acid were refluxed on a waterseparator for 4 hours. After cooling, the solution was extracted withNaHCO₃ and H₂O, and the extracts were dried over Na₂SO₄ and concentratedon a rotary evaporator.

Yield: 0.92 g, 79.75% of theory.

0.9 g of product were chromatographed over 50 g of silica gel. EluentCH₂Cl₂:MeOH=99:1

Fraction 1: 0.34 g of colorless foam (30.1% of theory)

Fraction 2: 0.19 g of colorless foam

Fraction 3: 0.17 g of colorless foam

TLC: CHCl₃:MeOH=95:5

Fraction 1:

¹H-NMR (CDCl₃): 6.95 (s, 1H), 5.38-5.60 (m, 2H), 4.64 (m, 1H), 4.15 (m,1H), 3.80 (s, 3H), 3.35-4.10 (m, 2H), 3.10 (s, 3H), 3.00 (dd, H), 2.85(dd, H), 2.15-2.35 (m, 2H), 1.70-1.95 (m, 2H), 1.12-1.25 (m, 3H).

Fraction 2:

¹H-NMR (CDCl₃): 0.96-1.1 (m, 3H), 1.18-1.32 (m, 3H), 1.40-1.71 (m, 2H),1.85 (b, H), 1.90-2.20 (m, 2H), 2.35-2.66 (m, 2H), 2.70-2.82 (m, H),3.10 (s, 3H), 3.20 (b, H), 3.42-3.81 (m, 6H), 3.85 (s, 3H), 4.02 (m, H),4.20 (m, H), 4.50 (bd, H), 7.05 (s, H).

Fraction 3:

¹H-NMR (CDCl₃): 0.95-1.1 (m, 3H), 1.20-1.35 (m, 3H), 1.51-1.72 (m, H),1.82 (b, H), 1.80-2.12 (m, 3H), 2.30-2.68 (m, 2H), 3.12 (s, 3H),3.20-3.75 (m, 7H), 3.83 (s, 3H), 3.96-4.15 (m, H), 4.22 (m, H), 4.52(bd, H), 7.07 (s, H).

EXAMPLE 36

Narwedine (general formula (Ia) with R₂=R₄=CH₃, X₁=X₂=H, Y₁,Y₂=O,Z₁=Z₂=H₂)

0.35 g of4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-12-oxo-6H-benzofuro-[3a,3,2-ef][2]benzazepine-6,6-propylene glycol ketal (general formula (Ia) withR₂=R₄=CH₃, X₁=Br, X₂=H, Y₁,Y₂=O—CH₂CH(CH₃)O—, Z₁=O, Z₂=H₂) were addedwith cooling to a solution of 0.2 g of LiAlH₄ in 20 ml of anhydrous THFand the mixture was stirred at room temperature overnight. Then 20 ml of2N HCl were added and the mixture was stirred at 40° C. for 30 minutes,rendered alkaline with concentrated NH₄OH and subjected to extractionwith ethyl acetate (4×30 ml). Drying over Na₂SO₄ and concentration ofthe organic phase by evaporation gave 0.21 g of yellowish oil which waschromatographed over 15 g of silica gel with CHCl₃/MeOH (98:2): 0.14 g(61.2% of theory) of narwedine as colorless crystals.

TLC: CHCl₃/MeOH (95:5)

EXAMPLE 37

Reduction of compound (12) with L-Selektride to a compound of thegeneral formula (Ia) with R₂=R₄=CH₃, X₁=Br, X₂=H, Y₁=OH, Y₂=H, Z₁=O,Z₂=H₂.

1 g of precursor (12) (0.0026 mol) was dissolved in 50 ml of anhydrousTHF, and then 7.93 ml of L-Selektride (0.0079 mol=3 eq.) were added andthe mixture was stirred at room temperature for three hours. Thesolution was acidified with 10 ml of 2N HCl, neutralized with 5 ml ofNH₄OH and subjected to extraction 3 times with ethyl acetate, and theextracts were dried over Na₂SO₄ and concentrated on a rotary evaporator.Yield: 1.07 g, 106.47% of theory.

The product was chromatographed with 50 g of silica gel, CHCl₃:MeOH=98:2

Yield Fr. 34-49:0.31 g

TLC: CHCl₃:MeOH=95:5

Melting point: 75.2-80° C.

¹H-NMR (CDCl₃): 1.65-1.80 (m, H), 1.95-2.17 (m, H), 2.19-2.38 (dt, H),2.65 (dm, H), 3.13-3.22 (m, H), 3.15 (s, 3H), 3.70-3.88 (m, H), 3.85 (s,3H), 4.12 (m, H), 4.70 (b,H), 5.50 (d, H), 5.88 (dd, H), 7.08 (s, H).

¹³C-NMR (CDCl₃): 29.64, 33.91, 38.01, 48.13, 48.63, 56.12, 60.59, 89.68,113.47, 117.78, 123.08, 126.20, 130.64, 131.90, 144.61, 146.02, 164.94.

Explanation of the abbreviations used in the

DiBAl-H: Diisobutylaluminum hydride

Red-Al^(R): Sodium bis-(2-methoxy-ethoxy)-aluminum dihydride

Superhydride^(R): Lithium trietylborohydride

9-BBN: 9-borabicyclo(3.3.1)nonane

L-Selektride^(R): Lithium tri-sec-butylborohydride (Aldrich)

K-Selektride^(R): Potassium tri-sec-butylborohydride (Aldrich)

LS-Selektride^(R): Lithium trisiamylborohydride (Aldrich)

KS-Selektride^(R): Potassium trisiamylborohydride (Aldrich)

Aliquat^(R): 3-methyl-trioctylammonium chloride

SV: Solvent

ML: Mother liquor

THF: Tetrahydrofuran

DMF: Dimethylformamide

EtOAc: Ethyl acetate

TsOH: p-Toluenesulfonic acid

RT: Room temperature

Literature

[1] D. H. R. Barton, G. W. Kirby, Proc. Chem. Soc. 392, 1960.

[2] D. H. R. Barton, G. W. Kirby, J. Chem. Soc. 806, 1962.

[3] T. Kametani, T. Yamaki, H. Yagi, K. Fukumoto, J. Chem. Soc. 2602,1969.

[4] T. Kametani, T. Yamaki, H. Yagi, K. Fukumoto, J. Chem. Soc. Chem.Comm. 25, 1969.

[5] T. Kametani, C. Seino, K. Yamaki, S. Shibuya, K. Fukumoto, K.Kigassawa, F. Satoh, M. Hiiragi, T. Hayasaka, J. Chem. Soc. (C), 1043,1971.

[6] T. Kametani, K. Yamaki, T. Terui, J. Het. Chem. 10, 35, 1973.

[7] T. Kametani, K. Shishido. E. Hayashi, C. Seino, T. Kohno, S.Shibuya, K. Fukumoto, J. Org. Chem. 36, 1295, 1971.

[8] J. Szewczyk, A. H. Lewin, F. I. Carroll, J. Het. Chem. 25, 1809,1988.

[9] Edinen Zentar po Chimia Sophia, DE 2945 161 800604, CA. 94, 15945b.

[10] Edinen Zentar po Chimia Sophia, U.S. Pat. No. 4,290,862 810,922,CA. 95, 212006t.

[11] R. Vlahov, D. Krikorian, V. Tarpanov, G. Spassov, G. Snatzke, H.Duddeck, H. J. Schäfer, K. Kieslich, Izv. Khim. 20, 59, 1987, CA. 108,150799e.

[12] D. Krikorian, R. Vlahov, S. Parushev, M. Chinova, I. Vlahov, H.Schäfer, H. Duddeck, G. Schnatzke, Tetrahedron Lett. 25, 2969, 1984.

[13] R. Vlahov, D. Krikorian, G. Spassov, M. Chinova, I. Vlahov. S.Parushev, G. Snatzke, L. Ernst, K. Kieslich, W. Abraham, W. Sheldrick,Tetrahedron 45, 3329, 1989.

[14] K. Shimizu, K. Tomioka, S. Yamada, K. Koga, Heterocycles 8, 277,1977.

[15] K. Shimizu, K. Tomioka, S. Yamada, K. Koga, Chem. Pharm. Bull. 26,3765, 1978.

[16] J. P. Yardley, H. Fletcher, Synth. 244, 1976.

[17] R. L. Edwards, D. V. Wilson, J. Chem. Soc. 5003, 1961.

[18] S. D. Saraf, Synth. Commun. 13, 7, 1983.

[19] B. Davis, M. Joullie, WO 8808708 A1.

[20] T. Kametani, M. Premila, K. Fukumotu, Heterocycles 4(6), 1111-14,1976.

[21] Synform 283-93, 1983.

[22] T. Kametani, K. Yamaki, H. Yagi, K. Fukumoto, J. Chem. Soc. C2601-5, 1969

[23] R. A. Holton, M. P. Sibi, W. S. Murphy, J.Am.Chem.Soc. 110, 314(1988)

[24] W. C. Shieh, J. A. Carlson, J. Org. Chem. 59, 5463-5465 (1994)

[25] A. B. Smith, S. J. Branca, M. A. Guaciaro, P. M. Wovkulich, A.Korn, Organic Synthesis Coll. Volume 7, 271.

[26] A. Hagedorn, D. Farnum, J. Org. Chem. 42, 3765 (1977).

What is claimed is:
 1. A compound of the formula VI:

wherein R₂, R₄, X₁ and X₂ are either identical or different and arehydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl or alkoxygroup, a lower, optionally branched alkyl group which is optionallysubstituted by at least one halogen, a lower, optionally branchedalkenyl group, a lower, optionally branched alkynyl group, an aryl,aralkyl or araloxyalkyl group, the alkyl chain of which is optionallybranched and the aromatic nucleus of which is optionally substituted,formyl or unbranched or branched alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,alkylsulfonyl, aralkylsulfonyl or arylsulfonyl which are unsubstitutedor substituted by one or more halogens, Z is O, and R₇ is selected fromthe group consisting of -OR₆, -SR₆, -OR₆OH, and -SR₆SH where R₆ isalkyl, alkenyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl oraralkylcarbonyl, optionally substituted with at least one halogen.
 2. Acompound selected from the group consisting of: